Cyclic amine bace-1 inhibitors having a heterocyclic substituent

ABSTRACT

Disclosed are novel compounds of the formula 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein
         R 1  is       

     
       
         
         
             
             
         
       
         
         
           
             X is —O—, —C(R 14 ) 2 — or —N(R)—; 
             Z is —C(R 14 ) 2 — or —N(R)—; 
             t is 0, 1, 2 or 3; 
             each R and R 2  is independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl or alkynyl; 
             each R 14  is H, alkyl, alkenyl, alkynyl, halo, —CN, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, —OR 35 , —N(R 24 ) (R 25 ) or —SR 35 ; 
             R 41  is alkyl, cycloalkyl, —SO 2 (alkyl), —C(O)-alkyl, —C(O)-cycloalkyl or -alkyl-NH—C(O)CH 3 ;
 
and the remaining variables are as defined in the specification.
 
           
         
       
    
     Also disclosed are pharmaceutical compositions comprising the compounds of formula I and methods of treating cognitive or neurodegenerative diseases with compounds of formula I. 
     Also disclosed are pharmaceutical compositions and methods of treatment comprising compounds of formula I in combination with other agents useful in treating cognitive or neurodegenerative diseases.

CROSS REFERENCE TO RELATED APPLICATION

This application is a Divisional application based on and claimingpriority to U.S. application Ser. No. 10/911,030, filed Aug. 4, 2004,which claims the benefit of U.S. Provisional Application 60/493,646,filed Aug. 8, 2003, each of which application is incorporated byreference.

FIELD OF THE INVENTION

This invention relates to substituted cyclic amine BACE-1 inhibitorshaving a heterocyclic substituent, pharmaceutical compositionscomprising said compounds, and their use in the treatment of Alzheimer'sdisease.

BACKGROUND

Alzheimer's disease (AD) is a progressive neurodegenerative disease thatis ultimately fatal. Disease progression is associated with gradual lossof cognitive function related to memory, reasoning, orientation andjudgment. Behavioral changes including confusion, depression andaggression also manifest as the disease progresses. The cognitive andbehavioral dysfunction is believed to result from altered neuronalfunction and neuronal loss in the hippocampus and cerebral cortex. Thecurrently available AD treatments are palliative, and while theyameliorate the cognitive and behavioral disorders, they do not preventdisease progression. Therefore there is an unmet medical need for ADtreatments that halt disease progression.

Pathological hallmarks of AD are the deposition of extracellularβ-amyloid (Aβ) plaques and intracellular neurofibrillary tanglescomprised of abnormally phosphorylated protein tau. Individuals with ADexhibit characteristic Aβ deposits, in brain regions known to beimportant for memory and cognition. It is believed that Aβ is thefundamental causative agent of neuronal cell loss and dysfunction whichis associated with cognitive and behavioral decline. Amyloid plaquesconsist predominantly of Aβ peptides comprised of 40-42 amino acidresidues, which are derived from processing of amyloid precursor protein(APP). APP is processed by multiple distinct protease activities. Aβpeptides result from the cleavage of APP by β-secretase at the positioncorresponding to the N-terminus of Aβ, and at the C-terminus byγ-secretase activity. APP is also cleaved by α-secretase activityresulting in the secreted, non-amyloidogenic fragment known as solubleAPP.

An aspartyl protease known as BACE-1 has been identified as theβ-secretase responsible for cleavage of APP at the positioncorresponding to the N-terminus of Aβ peptides.

Accumulated biochemical and genetic evidence supports a central role ofAβ in the etiology of AD. For example, Aβ has been shown to be toxic toneuronal cells in vitro and when injected into rodent brains.Furthermore inherited forms of early-onset AD are known in whichwell-defined mutations of APP or the presenilins are present. Thesemutations enhance the production of Aβ and are considered causative ofAD.

Since Aβ peptides are formed as a result β-secretase activity,inhibition of the BACE-1 enzyme should inhibit formation of Aβ peptides.Thus inhibition of BACE-1 is a therapeutic approach to the treatment ofAD and other cognitive and neurodegenerative diseases caused by Aβplaque deposition.

Substituted amine BACE-1 inhibitors are disclosed in WO 02/02505, WO02/02506, WO 02/02512, WP 02/02518 and WO 02/02520. Renin inhibitorscomprising a (1-amino-2 hydroxy-2-heterocyclic)ethyl moiety aredisclosed in WO 89/03842. WO 02/088101 discloses BACE inhibitorsfunctionally described as being comprised of four hydrophobic moieties,as well as series of compounds preferably comprising a heterocyclic orheteroaryl moiety.

SUMMARY OF THE INVENTION

The present invention relates to compounds having the structural formulaI

or a pharmaceutically acceptable salt or solvate thereof, wherein

R¹ is

X is —O—, —C(R¹⁴)₂— or —N(R)—;

Z is —C(R¹⁴)₂— or —N(R)—;

t is 0, 1, 2 or 3;

each R is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl and alkynyl;

R² is H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl,heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkenyl or alkynyl;

R³ is H or alkyl;

R⁴ is H or alkyl;

R⁵ is H, alkyl, cycloalkylalkyl, aryl or heteroaryl;

each R¹⁴ is independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, halo, —CN, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, heterocycloalkylalkyl, —OR³⁵, —N(R²⁴)(R²⁵) and —SR³⁵;

R⁴¹ is alkyl, cycloalkyl, —SO₂(alkyl), —C(O)-alkyl, —C(O)-cycloalkyl or-alkyl-NH—C(O)CH₃;

and wherein l, n, m, Y, and R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are asdefined in the following groups (A) to (C):(A) when l is 0-3; n is 0-3; m is 0 or m is 1 and Y is —C(R³⁰)(R³¹)—;and the sum of l and n is 0-3:

-   -   (i) R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are independently selected from        the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl,        aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,        heterocycloalkylalkyl, alkenyl, alkynyl, halo, —NO₂, —CN,        —N(R¹⁵)(R¹⁶), —OR¹⁷, —SR¹⁷, —C(O)R¹⁸, —N(R¹⁵)—C(O)R¹⁷,        —C(O)OR¹⁷, —C(O)N(R¹⁵)(R¹⁶), —O—C(O)R¹⁷ and —S(O)₁₋₂R¹⁸; and R¹²        and R¹³ are independently selected from the group consisting of        H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,        heterocycloalkyl, arylalkyl, heteroarylalkyl,        heterocycloalkylalkyl, alkenyl, alkynyl, —C(O)R¹⁸ and —C(O)OR¹⁷;

-   or (ii) R⁷ and R⁹, together with the ring carbons to which they are    attached, form a fused cycloalkyl or fused heterocycloalkyl group    and R⁶, R⁸, R¹⁰, R¹¹, R¹² and R¹³ are as defined in (A)(i); or R¹⁰    and R¹¹, together with the ring carbon to which they are attached,    form —C(O)—; or R¹² and R¹³, together with the ring carbon to which    they are attached, form —C(O)—;

-   or (iii) R⁶ and R⁷, together with the ring carbon to which they are    attached, form —C(═O)—, and R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are as    defined in (A)(i);

-   or (iv) R³ and R⁹, together with the ring carbon to which they are    attached, form —C(═O)—, and R⁶, R⁷, R¹⁰, R¹¹, R¹² and R¹³ are as    defined in (A)(i);    (B) when l is 1; n is 0-2; and m is 0:    -   R⁶ and R⁸, together with the ring carbons to which they are        attached, form a fused aryl group or a fused heteroaryl group,        R⁷ and R⁹ form a bond, and R¹⁰, R¹¹, R¹² and R¹³ are as defined        in (A)(i);        (c) when l is 0-3; n is 0-3; m is 1 and Y is —O—, —NR¹⁹—, —S—,        —SO— or —SO₂—; and the sum of l and n is 0-3:    -   R⁶, R⁷, R⁸, R⁹, R¹² and R¹³ are independently selected from the        group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,        heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,        heterocycloalkylalkyl, alkenyl, alkynyl, —C(O)N(R¹⁵)(R¹⁶),        —C(O)R¹⁸, —C(O)OR¹⁷ and —O—C(O)R¹⁷; and R¹⁰ and R¹¹ are as        defined in (A)(i), or R¹⁰ and R¹¹, together with the ring carbon        to which they are attached, form —C(O)—; or R¹² and R¹³,        together with the ring carbon to which they are attached, form        —C(O)—; or when Y is —O— or —NR¹⁹—, R⁶ and R⁷, together with the        ring carbon to which they are attached, form —C(O)—; or when Y        is —O— or —NR¹⁹—, R⁸ and R⁹, together with the ring carbon to        which they are attached, form —C(O)—;        wherein R¹⁵ is H or alkyl;

R¹⁶ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl,alkenyl or alkynyl;

or R¹⁵ and R¹⁶, together with the nitrogen to which they are attached,form a heterocycloalkyl ring;

R¹⁷ is H, alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl,arylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,alkenyl or alkynyl;

R¹⁸ is H, alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl,arylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,alkenyl, alkynyl or —N(R²⁴)(R²⁵);

R¹⁹ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl,—COR¹⁸, —C(O)OR⁴⁰, —SOR¹⁸, —SO₂R¹⁸ or —CN;

R²⁴ and R²⁵ are independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl and alkynyl;

or R²⁴ and R²⁵ together with the nitrogen to which they are attached,form a 3-7 membered heterocycloalkyl ring;

R³⁰ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, halo, —NO₂, —CN, —N(R¹⁵)(R¹⁶), —OR¹⁷, —SR¹⁷, —C(O)R¹⁸,—N(R¹⁵)—C(O)R¹⁷, —C(O)OR¹⁷, —C(O)N(R¹⁵)(R¹⁶), —O—C(O)R¹⁷ or —S(O)₁₋₂R¹⁸;

R³¹ is H or alkyl;

and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkenyl and alkynyl groups in R, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁴, R²⁵and R³⁰ are independently unsubstituted or substituted by 1 to 5 R³²groups independently selected from the group consisting of halo, alkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, —NO₂, —CN, haloalkyl,haloalkoxy, —N(R³³)(R³⁴), —NH(cycloalkyl), acyloxy, —OR³⁵, —SR³⁵,—C(O)R³⁶, —C(O)OR³⁵, —PO(OR³⁵)₂, —NR³⁵C(O)R³⁶, —NR³⁵C(O)OR³⁹,—NR³⁵S(O)₀₋₂R³⁹, and —S(O)₀₋₂R³⁹; or two R³² groups on the same ringcarbon atom in cycloalkyl, cycloalkylalkyl, heterocycloalkyl orheterocycloalkylalkyl together form ═O;

R³³ and R³⁴ are independently selected from the group consisting of Hand alkyl;

R³⁵ is H, alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl,arylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,alkenyl or alkynyl;

R³⁶ is H, alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl,arylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,alkenyl, alkynyl or —N(R³⁷)(R³⁸);

R³⁷ and R³⁸ are independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl and alkynyl;

or R³⁷ and R³⁸ together with nitrogen to which they are attached, form a3-7 membered heterocycloalkyl ring;

R³⁹ is alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocycloalkyl, heterocycloalkylalkyl, alkenyl or alkynyl; and

R⁴⁰ is alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl,heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkenyl oralkynyl.

In another aspect, the invention relates to a pharmaceutical compositioncomprising at least one compound of formula I and a pharmaceuticallyacceptable carrier.

In another aspect, the invention comprises the method of inhibitingBACE-1 comprising administering at least one compound of formula I to apatient in need of such treatment. Also claimed is the method ofinhibiting the formation, or formation and deposition, of β-amyloidplaques in, on or around neurological tissue (e.g., the brain)comprising administering at least one compound of formula I to a patientin need of such treatment.

More specifically, the invention comprises the method of treating acognitive or neurodegenerative disease comprising administering at leastone compound of formula I to a patient in need of such treatment. Inparticular, the invention comprises the method of treating a Alzheimer'sdisease comprising administering at least one compound of formula I to apatient in need of such treatment.

In another aspect, the invention comprises the method of treating acognitive or neurodegenerative disease comprising administering to apatient I need of such treatment a combination of at least one compoundof formula I and at least one compound selected from the groupconsisting of β-secretase inhibitors other than those of formula I,HMG-CoA reductase inhibitors, gamma-secretase inhibitors, non-steroidalanti-inflammatory agents, N-methyl-D-aspartate receptor antagonists,cholinesterase inhibitors and anti-amyloid antibodies.

In a final aspect, the invention relates to a kit comprising in separatecontainers in a single package pharmaceutical compositions for use incombination, in which one container comprises a compound of formula I ina pharmaceutically acceptable carrier and a second container comprises aβ-secretase inhibitors other than those of formula I, an HMG-CoAreductase inhibitor, a gamma-secretase inhibitor, a non-steroidalanti-inflammatory agent, an N-methyl-D-aspartate receptor antagonist, acholinesterase inhibitor or an anti-amyloid antibody in apharmaceutically acceptable carrier, the combined quantities being aneffective amount to treat a cognitive disease or neurodegenerativedisease such as Alzheimer's disease.

DETAILED DESCRIPTION

Referring to formula I, above, preferred compounds of the invention arethose wherein R³, R⁴ and R⁵ are hydrogen and R² is arylalkyl, alkyl orcycloalkylalkyl; more preferred are compounds wherein R² is optionallysubstituted benzyl, especially di-fluorobenzyl.

The R¹ portion of the compounds of formula I is preferably selected from

R¹ is more preferably (1),

with compounds wherein t is 1 and X is —C(R¹⁴)₂— or —N(R)— beingespecially preferred.

Additional preferred embodiments of R¹ are as follows:

wherein R is preferably alkyl, optionally substituted arylalkyl,alkenyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, orheteroarylalkyl, and R¹⁴ is preferably hydrogen, alkyl, alkenyl,cycloalkyl or benzyl. When R is arylalkyl in structure (1a), it ispreferably optionally substituted benzyl or optionally substitutedphenylethyl, wherein the optional substituents are 1 or 2 R³² groupsindependently selected from halo, alkyl, alkoxy and haloalkyl. Also,when R is heteroarylalkyl in structure (1a), the heteroaryl portion ispreferably selected from pyridyl, furanyl, thienyl or thiazolyl, and thealkyl portion is preferably methyl. Especially preferred R groups instructure (1a) are alkyl, alkoxyalkyl and cycloalkylalkyl; especiallypreferred R¹⁴ groups in structure (1a) are hydrogen and alkyl,particularly wherein one R¹⁴ is hydrogen and the other is hydrogen oralkyl.

wherein preferably each R is independently selected from the groupconsisting of hydrogen, alkyl, alkoxyalkyl, cycloalkylalkyl and benzyl.

wherein preferably R is hydrogen, alkyl, alkoxyalkyl, cycloalkylalkyl orbenzyl.

wherein each R is preferably independently selected from hydrogen,alkyl, alkoxyalkyl, cycloalkylalkyl and benzyl.

wherein preferably R is hydrogen, alkyl, alkoxyalkyl, cycloalkylalkyl orbenzyl.

wherein R⁴¹ is —C(O)-alkyl, —C(O)-cycloalkyl or —SO₂-alkyl.

wherein R is preferably hydrogen, alkyl, alkoxyalkyl, cycloalkylalkyl orbenzyl and R¹⁴ is preferably alkoxy.

When R¹ is

R is preferably alkyl, alkoxyalkyl, cycloalkylalkyl or benzyl and R¹⁴ ispreferably alkoxy.

Preferred R³² substituents are selected from the group consisting ofhalo, alkyl, OH, alkoxy, alkoxyalkyl, alkoxyalkoxy, haloalkyl,haloalkoxy, CN, cycloalkyl, cycloalkoxy, cycloalkylalkyl,cycloalkylalkoxy, phenyl and benzyl. Also preferred are compoundswherein two R³² substituents on the same ring carbon in a cycloalkyl,cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl group form═O.

The following are additional preferred embodiments of the invention:

-   -   1) compounds of formula I wherein R¹ to R⁵ are as defined above        in the summary of the invention and R⁶ to R¹³, l, m, n, and Y        are as defined in (A);    -   2) compounds of formula I wherein R¹ to R⁵ are the preferred        definitions defined above and R⁶ to R¹³, l, m, n, and Y are as        defined in (A);    -   3) compounds of formula I wherein R¹ to R⁵ are as defined above        in the summary of the invention and R⁶ to R¹³, l, m, n, and Y        are as defined in (B);    -   4) compounds of formula I wherein R¹ to R⁵ are the preferred        definitions defined above and R⁶ to R¹³, l, m, n, and Y are as        defined in (B);    -   5) compounds of formula I wherein R¹ to R⁵ are as defined above        in the summary of the invention and R⁶ to R¹³, l, m, n, and Y        are as defined in (C);    -   6) compounds of formula I wherein R¹ to R⁵ are the preferred        definitions defined above and R⁶ to R¹³, l, m, n, and Y are as        defined in (C).

In another embodiment, preferred are compounds of formula I, definition(A), wherein m is zero; the sum of l and n is 1 or 2; and R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each hydrogen; or wherein R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹ and R¹³ are each hydrogen and R¹² is methyl; or wherein R⁶, R⁷,R⁸, R⁹, R¹⁰ and R¹¹ are each hydrogen and R¹² and R¹³ together are ═O;or wherein R⁶, R⁷, R⁸, R⁹, R¹² and R¹³ are each hydrogen and R¹⁰ and R¹¹are ═O.

In another embodiment, preferred are compounds of formula I, definition(A), wherein m is zero; n is 1 and the sum of n and l is 1 or 2; R⁶, R⁹,R¹⁰, R¹¹, R¹² and R¹³ are each hydrogen; and R⁷ and R⁸ are as defined inthe summary of the invention. More preferred are compounds of formula I,definition (A), wherein m is zero; n is 1 and the sum of n and l is 1 or2; R⁶, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each hydrogen; and R⁷ and R⁸ areindependently selected from the group consisting of H and —OR¹⁷ whereinR¹⁷ is H, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; Apreferred definition for R¹⁷ is arylalkyl, especially benzyl, whereinthe aryl portion is optionally substituted with one or two substituentsindependently selected from the group consisting of halo and alkoxy.

In another embodiment, preferred are compounds of formula I, definition(A), wherein m is zero; l is 1; n is 1 or 2; R⁷ and R⁹ form a fusedcycloalkyl group; and R⁶, R⁸, R¹⁰, R¹¹, R¹² and R¹³ are each hydrogen.Preferably, R⁷, R⁹ and the carbons to which they are attached form acyclopropyl ring.

In another embodiment, preferred are compounds of formula I, definition(A), wherein m is 1; Y is —C(R³⁰)(R³¹)—; l is 0; n is 1; R⁶, R⁷, R⁸, R⁹,R¹² and R¹³ are each hydrogen; and R³⁰ and R³¹ are as defined in thesummary of the invention.

In another embodiment, preferred are compounds of formula I, definition(B), wherein m is zero; l is 1 and n is 1 or 2; R⁶ and R⁸ form a fusedaryl group; R⁷ and R⁹ form a bond; and R¹⁰, R¹¹, R¹² and R¹³ are eachhydrogen.

In another embodiment, preferred are compounds of formula I, definition(C), wherein m is 1; l is 0-3 and n is 0-3, provided that the sum of land n is 1-3; Y is —O—, —NR¹⁹—, —S—, —SO— or —SO₂—, wherein R¹⁹ isalkyl, arylalkyl or —SO₂R¹⁸, with preferred arylalkyl groups beingbenzyl and fluorobenzyl and preferred R¹⁸ groups being aryl andheteroaryl, especially phenyl, pyridyl, thienyl and imidazolyl; and R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each hydrogen, or R⁸, R⁹, R¹⁰,R¹¹, R¹² and R¹³ are each hydrogen and R⁶ and R⁷ together are ═O, or R⁶,R⁷, R⁹, R¹⁰, R¹¹ and R¹³ are each hydrogen and R⁸ and R¹² are as definedin the summary of the invention. More preferably, Y is —NR¹⁹— or —O—,with —NR¹⁹— being most preferred. In an especially preferred embodiment,m is 1; Y is —NR¹⁹—; l is 0; n is 1; R⁸, R⁹, R¹², and R¹³ are H; and R⁶and R⁷ together are ═O. In another especially preferred embodiment, m is1; Y is —NR¹⁹—; l is 0; n is 0; R⁸ and R⁹ are H; and R⁶ and R⁷ togetherare ═O.

Specific preferred embodiments of the cycloamino ring portion are:

wherein:R⁸ is H, OH, alkoxy, phenoxy or optionally substituted benzyloxy;R¹² is H or alkyl, preferably H;R¹⁹ is optionally substituted alkyl, —SO₂R¹⁸, —C(O)R¹⁸ or optionallysubstituted heteroarylalkyl, preferably alkyl, optionally substitutedbenzyl, benzoyl, (optionally substituted heteroaryl)alkyl, —SO₂alkyl,—SO₂(optionally substituted phenyl), —SO₂-naphthyl,(phenyl-alkenyl)-SO₂—, —SO₂— (optionally substituted benzyl), —SO₂—(optionally substituted heteroaryl), phenyl, —C(O)alkyl, —C(O)-(phenyl),—C(O)-heteroaryl, —C(O)N(alkyl)₂, —C(O)—O-benzyl, —SO₂— (optionallysubstituted heteroaryl), alkyl substituted by C(O)-heterocycloalkyl,alkyl-C(O)—N(alkyl)₂ and alkyl-C(O)—NH₂; andR³⁰ is —OC(O)-alkyl, optionally substituted phenyl, optionallysubstituted phenylalkyl, alkyl, alkoxy, cycloalkylalkyl,cycloalkylalkoxy, hydroxyalkoxy, dialkylaminoalkoxy, alkoxyalkoxy,optionally substituted heterocycloalkyl, heterocycloalkylalkyl,heterocycloalkylalkoxy, or —C(O)—O-alkyl, more preferably alkoxy oralkoxyalkoxy;wherein the optional substituents on phenyl are R³² substituentsselected from the group consisting of halo, alkyl, —C(O)CH₃, phenyl,—COO-alkyl, alkoxy, haloalkyl, phenoxy, —CN, —SO₂-alkyl and—NHC(O)alkyl; wherein the optional substituents on benzyl are R³²substituents selected from the group consisting of halo, alkyl, alkoxy,cyano and phenyl; and wherein heteroaryl is selected from the groupconsisting of pyridyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl,thienyl and imidazolyl and the optional substituents on heteroaryl areselected from alkyl, halo, —COO-alkyl, heteroaryl and —NHC(O)alkyl.

More preferred specific embodiments of the cyclic amino portion are

wherein the substituents are as defined in the paragraph immediatelyabove, with the former being especially preferred.

The preferred stereochemistry of compounds of formula I is that shown informula IA:

As used above, and throughout the specification, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising 1 to 20 carbon atoms in the chain. Preferredalkyl groups contain about 1 to about 12 carbon atoms in the chain. Morepreferred alkyl groups contain about 1 to about 7 carbon atoms in thechain. Branched means that one or more lower alkyl groups such asmethyl, ethyl or propyl, are attached to a linear alkyl chain. “Loweralkyl” means a group having about 1 to about 7 carbon atoms in the chainwhich may be straight or branched. Non-limiting examples of suitablealkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, n-pentyl, heptyl, nonyl and decyl. R³²-substituted alkyl groupsinclude fluoromethyl, trifluoromethyl and cyclopropylmethyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising 2 to 15 carbon atoms in the chain. Preferred alkenyl groupshave about 2 to about 12 carbon atoms in the chain; and more preferablyabout 2 to about 6 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl or propyl, are attached toa linear alkenyl chain. “Lower alkenyl” means about 2 to about 6 carbonatoms in the chain which may be straight or branched. Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.

“Aryl” (sometimes abbreviated “ar”) means an aromatic monocyclic ormulticyclic ring system comprising about 6 to about 14 carbon atoms,preferably about 6 to about 10 carbon atoms. The aryl group can beoptionally substituted with one or more R³² substituents which may bethe same or different, and are as defined herein. Non-limiting examplesof suitable aryl groups include phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one to four of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more R³²substituents which may be the same or different, and are as definedherein. The prefix aza, oxa or thia before the heteroaryl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively, ispresent as a ring atom. A nitrogen atom of a heteroaryl can beoptionally oxidized to the corresponding N-oxide. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, benzoxadiazolyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl areas previously described. Preferred aralkyls comprise a lower alkylgroup. Non-limiting examples of suitable aralkyl groups include benzyl,2-phenethyl and naphthalenylmethyl. The bond to the parent moiety isthrough the alkyl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising 3 to 10 carbon atoms, preferably about 5 to about 10 carbonatoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.The cycloalkyl can be optionally substituted with one or more R³²substituents which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkyls includecyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.Non-limiting examples of suitable multicyclic cycloalkyls include1-decalin, norbornyl, adamantyl and the like.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

Substituents on the rings defined above also include a cyclic ring of 3to 7 ring atoms of which 1-2 may be a heteroatom, attached to an aryl,heteroaryl or heterocyclyl ring by simultaneously substituting two ringhydrogen atoms on said aryl, heteroaryl or heterocyclyl ring.Non-limiting examples include:

and the like.

“Heterocyclyl” (or heterocycloalkyl) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which 1-3,preferably 1 or 2 of the atoms in the ring system is an element otherthan carbon, for example nitrogen, oxygen or sulfur, alone or incombination. There are no adjacent oxygen and/or sulfur atoms present inthe ring system. Preferred heterocyclyls contain about 5 to about 6 ringatoms. The prefix aza, oxa or thia before the heterocyclyl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively ispresent as a ring atom. The heterocyclyl can be optionally substitutedby one or more R³² substituents which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and thelike.

“Heteroarylalkyl” means a heteroaryl-alkyl- group in which theheteroaryl and alkyl are as previously described. Preferredheteroarylalkyls contain a lower alkyl group. Non-limiting examples ofsuitable heteroarylalkyl groups include pyridylmethyl,2-(furan-3-yl)ethyl and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, alkynyl-C(O)— orcycloalkyl-C(O)— group in which the various groups are as previouslydescribed. The bond to the parent moiety is through the carbonyl.Preferred acyls contain a lower alkyl. Non-limiting examples of suitableacyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl,butanoyl and cyclohexanoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.The bond to the parent moiety is through the ether oxygen.

“Fused cycloalkyl” means that a cycloalkyl ring is fused to the cyclicamino portion of compounds of formula I, e.g., a compound having thestructure

Similarly, “fused heterocycloalkyl” means that a heterocycloalkyl groupis fused to the cyclic amino portion of compounds of formula I, e.g., acompound having the structure

When “Y” is a heteroatom, R⁷, R⁹ and the carbons to which they areattached can form a fused ring wherein “Y” is the only heteroatom, orR⁷, R⁹ and the carbons to which they are attached can form a ringcomprising one or two additional heteroatoms, e.g.,

“Fused aryl” means that an aryl group is fused to the cyclic aminoportion of compounds of formula I, e.g., a compound having the structure

“Fused heteroaryl” means a similar structure, wherein, for example, thephenyl ring is replaced by pyridyl.

The cycloamino ring portion of the compounds of formula I, i.e., theportion of the compound having the structure

can have 1 or 2 oxo substituents, that is, where R¹⁰ and R¹¹, or R⁶ andR⁷, or R⁸ and R⁹, or R¹² and R¹³ form —C(O)— groups with the carbons towhich they are attached, one or two such groups can be present on thering as long the conditions in (C) are met (i.e., a —C(O)— group is notadjacent to Y=S(O)₀₋₂—). For example, R⁶ and R⁷, and R¹² and R¹³ caneach form —C(O)— groups with the carbons to which they are attached whenm is 0 and R⁸, R⁹, R¹⁰ and R¹¹ are hydrogen.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties, in available position orpositions.

With reference to the number of moieties (e.g., substituents, groups orrings) in a compound, unless otherwise defined, the phrases “one ormore” and “at least one” mean that there can be as many moieties aschemically permitted, and the determination of the maximum number ofsuch moieties is well within the knowledge of those skilled in the art.With respect to the compositions and methods comprising the use of “atleast one compound of formula I,” one to three compounds of formula Ican be administered at the same time, preferably one.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The wavy line

as a bond generally indicates a mixture of, or either of, the possibleisomers, e.g., containing (R)- and (S)-stereochemistry. For example,

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples, structural formulae, and any Tables hereinis assumed to have the hydrogen atom or atoms to satisfy the valences.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of formula I or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, both of which are incorporated herein by referencethereto.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting BACE-1 and thus producing the desiredtherapeutic effect in a suitable patient.

The compounds of formula I form salts which are also within the scope ofthis invention. Reference to a compound of formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the formula I may be formed, for example, by reacting a compound offormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization. Acids (and bases) which are generallyconsidered suitable for the formation of pharmaceutically useful saltsfrom basic (or acidic) pharmaceutical compounds are discussed, forexample, by S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website); and P. HeinrichStahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (2002) Int'l. Union of Pure and AppliedChemistry, pp. 330-331. These disclosures are incorporated herein byreference thereto.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, methyl sulfates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates, sulfonates (such as those mentionedherein), tartarates, thiocyanates, toluenesulfonates (also known astosylates,) undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, aluminum salts, zinc salts, salts withorganic bases (for example, organic amines) such as benzathines,diethylamine, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, piperazine,phenylcyclohexylamine, choline, tromethamine, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quaternized with agents such as lower alkyl halides (e.g. methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of formula I, and salts, solvates and prodrugs thereof, mayexist in their tautomeric form (for example, as an amide or iminoether). All such tautomeric forms are contemplated herein as part of thepresent invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate” “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the inventive compounds.

For the combination aspect, the use of any β-secretase inhibitor otherthan those of formula I is contemplated; β-secretase inhibitory activitycan be determined by the procedures described below. Typical β-secretaseinhibitors include, but are not limited to, those disclosed in WO02/02505, WO 02/02506, WO 02/02512, WO 02/02518, WO 02/02520 and WO02/088101.

Gamma-secretase inhibitors for use in the combination of this inventioncan be determined by procedures known in the art. Typicalgamma-secretase inhibitors include, but are not limited to, thosedescribed in WO 03/013527, U.S. Pat. No. 6,683,091, WO 03/066592, U.S.Ser. No. 10/663,042, filed Sep. 16, 2003, WO 00/247671, WO 00/050391, WO00/007995 and WO 03/018543.

HMG-CoA reductase inhibitors for use in combination with compounds offormula I include the “stains,” e.g., atorvastatin, lovastatin,simvistatin, pravastatin, fluvastatin and rosuvastatin.

Cholinesterase inhibitors for us in the combination include acetyl-and/or butyrylcholinesterase inhibitors. Examples of cholinesteraseinhibitors are tacrine, donepezil, rivastigmine, galantamine,pyridostigmine and neostigmine.

Non-steroidal anti-inflammatory agents for use in combination withcompounds of formula I include ibuprofen, naproxen, diclofenac,diflunisal, etodolac, flurbiprofen, indomethacin, ketoprofen, ketorolac,nabumetone, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib androfecoxib. A suitable N-methyl-D-aspartate receptor antagonist is, forexample, memantine. Anti amyloid antibodies are described, for example,in Hock et al, Nature Medicine, 8 (2002), p. 1270-1275.

Compounds of formula I can be made using procedures known in the art.The following reaction schemes show typical procedures, but thoseskilled in the art will recognize that other procedures can also besuitable. In the Schemes and in the Examples below, the followingabbreviations are used:

-   methyl: Me; ethyl: Et; propyl: Pr; butyl: Bu; benzyl: Bn-   high pressure liquid chromatography: HPLC-   liquid chromatography mass spectroscopy: LCMS-   thin layer chromatography: TLC-   preparative thin layer chromatography: PTLC-   room temperature: RT-   hour: h-   minute: min-   retention time: t_(R)-   1-hydroxybenzotriazole: HOBt-   1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide: EDCl-   1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: EDC-   benzotriazole-1-yl-oxy-trispyrrolidinophosphonium    hexafluorophosphate:-   PyBOP-   ethyl acetate: EtOAc-   tetrahydrofuran: THF-   N,N-dimethylformamide: DMF-   n-butyllithium: n-BuLi-   1-hydroxy-1-oxo-1,2-benzodioxol-3(1H)-one: IBX-   triethylamine: NEt₃ or Et₃N-   dibutylboron triflate: Bu₂BOTf-   methanol: MeOH-   diethyl ether: Et₂O-   acetic acid: AcOH-   diphenylphosphoryl azide: DPPA-   isopropanol: iPrOH-   benzyl alcohol: BnOH-   1-hydroxy-7-azabenzotriazole: HOAt-   O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate: HATU-   trifluoroacetic acid: TFA-   tertiary butyloxycarbonyl: Boc-   benzyloxycarbonyl: Cbz-   dimethylsulfoxide: DMSO-   diisopropylethylamine: DIEA-   lithium diisopropylamide: LDA tris-(2-aminoethyl)aminomethyl    polystyrene (PS-trisamine)-   methylisocyanate polystyrene (PS-NCO)

General Schemes:

In Scheme 1, a cyclic amine 2-carboxaldehyde derivative is added to anEvans acyl oxazolidinone bearing an appropriate R² group. Cleavage ofthe oxazolidinone product II and Curtius rearrangement of the resultantcarboxylic acid III affords an oxazolidinone IV. Base hydrolysis of theoxazolidinone IV to give V and derivatization of the primary amine of Vby, for example, acylation, affords an intermediate VIII. Removal of thecyclic amine protecting group gives the desired product.

Alternatively, VI is formed by protection of the hydroxyl group of III.Curtius rearrangement of VI and trapping of the intermediate isocyanatewith benzyl alcohol affords VII which can be deprotected to giveintermediate V.

In the schemes, the variable “R^(x)” is used in place of variablesR⁶-R¹³ in order to simplify the structures. “PG” refers to an amineprotecting group. Examples of suitable amine protecting groups are Bocand Cbz; Bn can also be used for secondary amines, and (Bn)₂ can also beused for primary amines (in which case, the PG-NH— portion of thestructures shown in the schemes below would become (PG)₂-N—, i.e.,(Bn)₂-N—).

Scheme 2 shows another method of synthesis of the desired compounds,wherein the anion generated from a 3-oxo cyclic amine derivative isadded to a protected α-amino aldehyde derivative to give an adduct IX.Deprotection of IX, followed by derivatization of the primary amine,followed by cyclic amine protecting group removal, affords the desiredproduct.

In Scheme 3, a lithio derivative of a 2-halopyridine is added to aprotected α-amino aldehyde derivative to give an adduct X. The protectedprimary amine of X is deprotected and the resultant amine is acylated tothe desired derivative XI. Hydrogenation of the pyridine ring affords apiperidine derivative, the nitrogen of which can be protected for easeof purification to give XII. Deprotection of the cyclic amine XII givesthe desired product.

In Scheme 4, a 2-lithio derivative of 4-chloropyridine is added to aprotected amino aldehyde to give the intermediate XIII. The chlorosubstituent of XIII can be displaced by an alkoxide (R^(17X)—OH, whereinR^(17X) is as defined for R¹⁷, but not H) to give an ether XIV.Deprotection and derivatization of the primary amine, followed byreduction of the pyridine ring gives the corresponding piperidineproduct.

In Scheme 5, lithiated XV is added to a protected N,N-dibenzylaminoaldehyde to give a product XVI. Removal of the N,N-dibenzylprotecting group from XVI by hydrogenolysis followed by reduction of thepiperazinone oxo group with borane-dimethylsulfide gives a piperazineproduct XVII. Derivatization of the primary amine of XVII andhydrogenolysis of the piperazine benzyl group gives intermediate XVIII.Derivatization of the piperazine nitrogen of XVIII followed bydeprotection gives the piperazine product.

Scheme 6 is a variation of Scheme 5, wherein the oxo group of XVI isremoved by reduction with borane-dimethyl sulfide followed by removal ofthe N-benzyl groups to give a diamine XIX. Introduction of R^(x) byderivatization of the secondary amine of XIX to give XX, followed byintroduction of R¹ and deprotection gives the products. Alternatively,the primary amine of XIX can be protected by imine formation to giveXXI. Introduction of R^(x) by derivatization of the secondary amine ofXXI, followed by deprotection of the primary amine gives XXII.Intermediate XXII is derivatized by introduction of R¹ and deprotectionto give the desired product.

The conditions for the LCMS and RP-HPLC analyses in the preparations andexamples below are as follows:

Conditions A: 5 minute gradient from 10%→95% CH₃CN/H₂O with 0.1% TFA,then 2 min isocratic at 95% CH₃CN/H₂O with 0.1% TFA, 1.0 ml/min flowrate on an analytical C18 reverse phase column.Conditions B: gradient from 10%→95% CH₃CN/H₂O with 0.1% HCO₂H, 25 ml/minflow rate on a preparative C18 reverse phase column.Conditions C: gradient from 5%→95% CH₃CN/H₂O with 0.1% HCO₂H, 20 ml/minflow rate on a a preparative C18 reverse phase column.

Preparation 1

According to the literature (Kruse et al., J. Med. Chem. (1987), 30,486-494), a solution of 3,5-difluorocinnamic acid (9.94 g, 53.9 mmol) inTHF (100 ml) was hydrogenated over 10% Pd/C (1.50 g) at 50 psi of H₂pressure for 5 h. The mixture was filtered and concentrated underreduced pressure to yield the 3-(3,5-difluoro-phenyl)propionic acid(10.9 g, 100%). Oxalyl chloride (13 ml, 150 mmol) was slowly added to asolution of the acid (10.9 g, 53.9 mmol) in THF (220 ml) at 23° C.,followed by the addition of a catalytic amount of DMF (1 drop). After 90min, the volatiles were removed under reduced pressure and the resultingresidue was twice coevaporated with dry benzene to yield3-(3,5-difluorophenyl)-propionyl chloride as a yellow oil (11.91 g,100%). The acid chloride was used in the ensuing step without furtherpurification. The acylation was carried out in analogy to the literature(Pettit et al. Synthesis, (1996), 719-725). A solution of(S)-(−)-4-isopropyl-2-oxazolidinone (6.46 g, 50 mmol) in THF (150 ml)was stirred under argon and cooled to −78° C. n-BuLi (2.45 M in hexanes,20.8 ml, 50.96 mmol) was added dropwise, followed by a solution of thepreviously prepared 3-(3,5-difluorophenyl)-propionyl chloride in THF (8ml). After warming the reaction to 23° C. over 15 h, the reaction wasquenched with saturated aq. NH₄Cl (30 ml), followed by removal of thevolatiles in vacuo. The slurry was extracted with CH₂Cl₂ (×2), and thecombined organic layers washed with NaOH (×2) and brine, dried (Na₂SO₄)and concentrated in vacuo. Purification of the residue by chromatographyover silica gel (15→30% EtOAc/hexanes) gave the product (14.27 g, 48mmol, 96%). ¹H NMR (400 MHz, CDCl₃): δ=6.73 (m, 2H), 6.59 (m, 1H), 4.37(m, 1H), 4.17-4.25 (m, 2H), 3.24 (m, 1H), 3.16 (m, 1H), 2.93 (m, 2H),2.30 (m, 1H), 0.86 (d, 3H, J=6.8 Hz), 0.80 (d, 3H, J=6.8 Hz); LCMS(Conditions A): t_(R)=4.47 min: 595 (2M+H), 298 (M+H).

Preparation 2A

A mixture of itaconic acid (13.0 g, 100 mmol) and n-butylamine (7.31 g,100 mmol) in toluene (100 ml) was heated in a sealed tube at 120° C. for22 h. The mixture was cooled to RT and 1N NaOH (400 ml) was added. Theaqueous layer was washed with Et₂O (2×200 ml), acidified with conc. HCl(40 ml), and extracted with Et₂O (3×200 ml). The combined Et₂O layer waswashed with brine, dried over Na₂SO₄, concentrated, and dried in vacuoto give the product (12.0 g, 65%). MS m/e 186 (M+H)⁺.

Using an analogous procedure and the appropriate amine, the followingacids were prepared in racemic form, unless otherwise indicated:

Preparation 2JJ

Step 1:

A mixture of itaconic acid (13.0 g, 100.0 mmol) and allyl amine (5.71 g,100 mmol) in anhydrous toluene (100 ml) was heated in a sealed tube at125° C. for 16 h. After the mixture was cooled down to RT, 1N aqueousNaOH (400 ml) was added and the aqueous layer was extracted with ether(2×200 ml). The aqueous layer was acidified with conc. HCl to pH 1 andextracted with ether (10×300 ml). The combined organic portion wasconcentrated and the residue was dissolved with CH₂Cl₂ (200 ml) andwashed with brine. The organic layer was dried with MgSO₄, concentrated,and lyophilized to give a light yellow solid (9.60 g, 57%). MS m/e 170(M+H)⁺.

Step 2:

To a solution of the product of Step 1 (8.60 g, 50.9 mmol) and Et₃N(15.4 g, 153 mmol) in anhydrous THF (200 ml) at −45° C. was addedpivaloyl chloride (6.45 g, 53.5 mmol). The mixture was stirred at −45°C. for 1 h and then added into a suspension of LiCl (4.75 g, 112 mmol)and (S)-4-benzyl-2-oxazolidinone (9.02 g, 50.9 mmol) in THF (100 ml).The resulting mixture was stirred at RT for 16 h and filtered. Thefiltrate was concentrated, dissolved in EtOAc (700 ml), and washed with1N HCl (200 ml), sat'd NaHCO₃ (200 ml), and brine. The organic layer wasdried (MgSO₄), concentrated, and purified by column chromatography(SiO₂, gradient 0-75% EtOAc/Hexanes) to give the product (7.20 g, 43%).MS m/e 329 (M+H)⁺.

Step 3:

To a solution of the product of Step 2 (2.63 g, 8.01 mmol) in THF (30ml) and water (8 ml) in an ice-water bath was added 30% H₂O₂ (4 ml) andLiOH (0.672 g, 16.0 mmol). The mixture was stirred at 0° C. for 7 h. 10%Aqueous sodium bisulfite (40 ml) was added and the mixture was stirredat RT for 16 h. The mixture was concentrated and the residue waspartitioned between 1N NaOH (8 ml) and CH₂Cl₂ (2×100 ml). The aqueouslayer was acidified to pH 2 at 0° C. and extracted with ether (5×100ml). The combined organic portion was dried (MgSO₄) and concentrated togive the product (1.00 g, 74%). MS m/e 170 (M+H)⁺.

Using the appropriate starting lactam and essentially the same procedurethe following Preparations were obtained.

Preparation 3A

Step 1:

To an ice-cold solution of Preparation 2A (1.148 g, 6.20 mmol) inanhydrous THF (20 ml) was added 1.0M lithium bis(trimethylsilyl)amide inhexanes (13.0 ml). The mixture was stirred in ice-water bath for 30min., at RT for 2 h, and then cooled in a dry ice-acetone bath.Iodoethane was added and the mixture was allowed to warm to RT slowlyand stirred for 16 h. The mixture was diluted with EtOAc (45 ml) andwashed with ice-cold water (60 ml). The aqueous layer was acidified withconc. HCl to pH=1-2 and extracted with EtOAc (2×60 ml). The combinedorganic layer was washed with brine (30 ml), dried (MgSO₄), andconcentrated. The residue was taken up in CH₂Cl₂ (20 ml) and oxalylchloride (0.53 ml, 6.0 mmol) was added along with 3 drops of DMF. Thereaction mixture was stirred at RT for 16 h then cooled in an ice-waterbath. To this reaction mixture was added Et₃N (1.7 ml, 12 mmol) andbenzyl alcohol (0.875 g, 8.09 mmol). After stirring at RT for 24 h, themixture was diluted with CH₂Cl₂ (50 ml) and washed with 5% citric acid(60 ml) and saturated NaHCO₃ solution (50 ml). The organic layer wasdried (MgSO₄), concentrated, and purified by column chromatography(gradient hexanes to 1:4 EtOAc/hexanes) to give the product (0.608 g,32%). MS m/e 304 (M+H)⁺.

Step 2:

A mixture of the product of Step 1 (0.608 g) and 10% Pd/C (0.06 g) inEtOH (20 ml) was stirred under H₂ (1 atm) for 16 h. The mixture wasfiltered through a pad of Celite and concentrated to give the product(0.441 g, 100%). MS m/e 214 (M+H)⁺.

Using an appropriate alkyl halide and an analogous procedure, thefollowing acids were prepared:

Preparations 3H-3M

Carboxylic acids 3H-3N were prepared in analogy to the publishedprocedure (Baltaief et al., Tetrahedron, 1999, 55, 3949).

Preparation 4

step 1:

A mixture of benzyl (S)-2-oxazolidinone-5-carboxylate (750 mg, 3.39mmol; prepared according to K. Danielmeier et al, Tetrahedron:Asymmetry, (1995), 6, 1181-1190), crotyl bromide (2.02 g, 15.0 mmol),and anhydrous K₂CO₃ (1.88 g, 13.6 mmol) in anhydrous acetone (20 ml) wasstirred at RT for 24 h. The mixture was filtered and concentrated. Theresidue was dissolved in CH₂Cl₂ (100 ml), washed with water and brine,dried (MgSO₄), concentrated, and purified by column chromatography(CH₂Cl₂) to give the title compound (480 mg, 51%). MS m/e 276 (M+H)⁺.

Step 2:

A mixture of the product of Step 1 (480 mg, 1.74 mmol) and 10% Pd/C (48mg) in MeOH (25 ml) was stirred under H₂ (1 atm) for 3.5 h. The mixturewas filtered and concentrated to give the title compound (340 mg, 100%).MS m/e 188 (M+H)⁺.

Preparation 5A

Step 1:

To a stirred ice-cold solution of tert-butyl(4S)-3-(benzyloxycarbonyl)-2-oxoimidazolidine-4-carboxylate (Hayashi etal., J. Med. Chem. 1989, 32, 289) (0.64 g, 2 mmol) in DMF (8 ml) wasadded NaH (60% dispersion, 84 mg, 2.1 mmol). After 40 min MeI (0.62 ml,10 mmol) was added and the reaction mixture was allowed to warm to RT.After 16 h the reaction mixture was concentrated and the residue waspartitioned between EtOAc (20 ml) and water. The organic layer waswashed with sat'd NaCl, dried (MgSO₄), filtered and evaporated. Theresidue was subjected to column chromatography (SiO₂; hexanes—2:3EtOAc/hexanes) to give the product (345 mg).

Step 2:

The product of Step 1 (335 mg, 1 mmol) and 10% Pd/C in MeOH (15 ml) wasstirred under an atmosphere of H₂ for 18 h. The reaction mixture wasfiltered and the filtrate was evaporated to give the product (183 mg).

Step 3:

To an ice-cold suspension of NaH (60% dispersion, 35 mg, 0.9 mmol) inDMF (3 ml) was added a solution of the product of Step 2 (173 mg, 0.87mmol) in DMF (2 ml). After 0.5 h, 1-iodopentane (0.57 ml, 4.3 mmol) wasadded and the resulting mixture was stirred at RT for 16 h. The reactionmixture was concentrated then partitioned between EtOAc (20 ml) andwater. The organic layer was washed with sat'd NaCl, dried (MgSO₄),filtered and evaporated. The residue was subjected to columnchromatography (SiO₂; hexanes—2:3 EtOAc/hexanes) to give the product(205 mg).

Step 4:

The product of Step 3 (200 mg, 0.74 mmol) in 1:4 TFA/CH₂Cl₂ (5 ml) wasstirred for 2 days. The reaction mixture was evaporated and the residuewas taken up in 1N HCl in Et₂O (2 ml), then evaporated to give theproduct (209 mg).

By using an analogous procedure to that of Preparation 5A, the followingacids were prepared

Preparation 6

To a solution of 1-propylamine (1.68 ml, 20.5 mmol) in CH₃CN (10 ml) wasadded a solution ethyl 2-(bromomethyl)acrylate (1.32 g, 6.8 mmol) inCH₃CN (20 ml). After 18 h, Et₂O (100 ml) was added and the suspensionwas filtered. The filtrate was evaporated and the residue was taken upin EtOAc, washed with water and sat'd NaCl, dried (MgSO₄), filtered andevaporated to give a yellow oil (1.27 g). A mixture of this product (634mg, 2.75 mmol) and carbonyldiimidazole (535 mg, 3.30 mmol) in THF (14ml) was stirred for 0.75 h. The reaction mixture was partitioned betweenEtOAc (100 ml) and 1N HCl. The organic layer was washed with 1N HCl,sat'd NaCl, dried (MgSO₄), filtered and evaporated to give a yellow oil(131 mg). This oil was dissolved in THF (3 ml) and 3N NaOH (0.7 ml) wasadded. After 18 h, the reaction mixture was acidified with 6N HCl,concentrated, and the residue was subjected to reverse-phase HPLC(Conditions B) to give the product (46 mg) as a white solid.

Preparation 7

Step 1:

A THF-solution of 1-Boc-piperazin-3-one at 0° C. was treated with NaH(1.5 equiv) and propyl iodide (2 equiv). After stirring the reaction for18 h at RT, the reaction was quenched with water, acidified with 1 MHCl, and washed with sat'd NaHCO₃. The organic layer was dried (MgSO₄),concentrated, and purified by column chromatography (SiO₂, gradient 4%to 11% hexanes/i-PrOH) to give the alkylated product. Treatment of thisproduct with 20% TFA/CH₂Cl₂, followed by removal of volatiles in vacuogave the product as a salt.

Step 2:

Et₃N (3 equiv) was added to a THF-solution of the product of Step 1 atRT, followed by carbonyldiimidazole (1.2 equiv). The reaction was heatedfor 18 h at 50° C., then cooled to RT and diluted with EtOAc. Theorganic layer was sequentially washed with water (4×) and sat'd NaCl(1×), then dried (MgSO₄) and concentrated under vacuum. The resultingresidue was dissolved in CH₃CN and treated with excess CH₃I for 6 h atRT. After concentrating the reaction in vacuo, the product was obtainedas a yellow foam that was used directly.

Preparation 8

Step 1:

(R)-Nipecotic acid (1.05 g, 8.1 mmol) was dissolved in THF (20 ml) andH₂O (20 ml). (Boc)₂O (2.48 g, 11.4 mmol) and NaHCO₃ (0.96 g, 11.4 mmol)was added. The mixture was stirred at RT overnight. The mixture wasdiluted with H₂O and ether. The aqueous layer was adjusted to pH=2 withconcentrated HCl and extracted with CH₂Cl₂. The organic layers werecombined, dried (Na₂SO₄), and concentrated to give N-Boc-(R)-nipecoticacid (1.8 g, 97%). LCMS (Conditions A) t_(R)=3.26 min, 230 (M+H).

Step 2:

To a solution of the product of Step 1 (1.8 g, 7.9 mmol) anddipropylamine (10.9 ml, 78.6 mmol) in DMF (8 ml) were added PyBOP (5.32g, 10.2 mmol) and DIEA (4.12 ml, 23.6 mmol). The mixture was stirred atRT overnight. It was diluted with EtOAC and hexane. After the mixturewas washed with H₂O, the organic layer was dried over Na₂SO₄ andconcentrated. The crude residue was purified by chromatography (SiO₂,20% EtOAc/hexane) to give the product (2.19 g, 89%). ¹H NMR (400 MHz,CDCl₃) δ 4.04 (m, 2H), 3.38-3.00 (m, 4H), 2.95-2.40 (m, 3H), 1.80-1.50(m, 8H), 1.39 (s, 9H), 0.875 (t, 3H, J=7.2 Hz), 0.803 (t, 3H, J=7.2 Hz).LCMS (Conditions A) t_(R)=4.50 min, 313 (M+H).

Step 3:

The product of Step 2 was subjected to 1:4 TFA/CH₂Cl₂ to remove the Bocgroup, then converted to Preparation 8 by essentially the procedure ofPreparation 7, Step 2.

Preparation 9

Step 1:

CsOH—H₂O (1.2 equiv) and 4 Å molecular sieves (70 mg/mmol substrate)were added sequentially to a DMF solution of3-(R)-hydroxy-1-Boc-pyrrolidine at RT. After 10 min, allyl bromide (2.0equiv) was added and stirring continued for 18 h. The reaction wasdiluted with EtOAc, filtered, and acidified with 1 M HCl. The organiclayer was washed with sat'd aq NaHCO₃ (2×) and sat'd NaCl (1×), thendried (MgSO₄) and concentrated. The residue was subjected to columnchromatography (SiO₂, 2% to 4% i-PrOH/hexanes) to give the alkylatedintermediate. Pd(OH)₂ was added to a solution of this intermediate inMeOH, and the suspension was stirred under H₂ for 18 h. The catalyst wasremoved by filtration and the filtrate was concentrated. The residue wastreated with 20% TFA/CH₂Cl₂ at RT for 2 h, then evaporated in vacuo togive the product as a salt (100%).

Step 2:

The product of Step 1 was converted to Preparation 9 by essentially thesame procedure set forth in Preparation 7, Step 2.

Preparation 10A

Step 1:

To an ice-cold solution of ethyl 2(S)-4,4-diallylpyroglutamate, whichwas prepared from ethyl2(S)-1-(tert-butoxycarbonyl)-4,4-diallylpyroglutamate, (Ezquerra et al.,J. Org. Chem., (1994), 59, 4327; 1.2 g, 3.6 mmol) and methyl iodide(0.25 ml, 4 mmol) in anhydrous THF (18 ml) was added NaH (60%dispersion; 216 mg, 6 mmol). After 0.5 h, the reaction mixture wasallowed to warm to RT and stirred for 1 h. The reaction mixture wasquenched with sat'd NaCl, and extracted with Et₂O (×2). The combinedorganic layers were washed with sat'd NaCl, dried (MgSO₄), filtered andevaporated to give the methylated product (1.2 g) as an oil. This oilwas dissolved in THF (20 ml) and 3 N NaOH (5 ml) was added. After 22 h,the reaction mixture was acidified with 6 N HCl and extracted with Et₂O(×3). The combined organic layers were dried (MgSO₄), filtered andevaporated. Preparative HPLC (Conditions B) gave the product (215 mg) asan oil.

Preparation 10B

In analogy to Preparation 10A, Preparation 10B was obtained.

Preparation 11

Step 1:

(2S,4S)-N-benzyloxycarbonyl-4-hydroxyproline methyl ester was treatedwith NaH/DMF and allyl bromide. The resulting intermediate in MeOH wasstirred under 50 psi H₂ in the presence of 20% Pd(OH)₂/carbon andcatalytic AcOH. After filtration and evaporation the product wasobtained.

Step 2:

A mixture of the product of Step 1, 37% aqueous HCHO, NaOAc and 20%Pd(OH)₂/C in MeOH was stirred under 50 psi H₂. After 20 h at RT, thereaction mixture was filtered, concentrated, then dissolved in 3 M HCl.The aqueous layer was washed with Et₂O (2×), and basified with NaHCO₃.After extracting with CH₂Cl₂ (3×), the organic layer was dried (MgSO₄),and concentrated. The residue was treated with 3 M NaOH/THF for 18 h atRT. After acidifying the reaction mixture with 4 M HCl/dioxane, themixture was extracted with CH₂Cl₂, and the organic layer concentrated togive the product mixture that was used directly.

Preparation 12

Step 1

To a stirred, ice-cold solution of n-butylamine (3.29 g, 45 mmol) inMeOH (20 ml) was added an ice-cold solution of methyl coumalate (3.08 g,20 mmol) in MeOH (25 ml) dropwise. After 18 h the reaction mixture wasconcentrated and the residue was subjected to column chromatography(SiO₂; 0%-1.5% MeOH/CH₂Cl₂) to give the product (2.3 g).

Step 2:

A mixture of the product of Step 1 (1.34 g, 6.4 mmol) and PtO₂ (134 mg)in MeOH (100 ml) was stirred under 50 psi H₂ for 24 h. Additional PtO₂(400 mg) was added and the reaction mixture was stirred under 50 psi H₂for 6 h. The reaction mixture was filtered and the filtrate wasconcentrated. Column chromatography of the residue (SiO₂; 0%-2%MeOH/CH₂Cl₂) gave methyl 1-butyl-6-oxopiperidine-3-carboxylate (820 mg).A mixture of methyl 1-butyl-6-oxopiperidine-3-carboxylate (800 mg, 3.8mmol) and 1N NaOH (7.5 ml) in MeOH (15 ml) was stirred at RT for 1 h.The reaction mixture was acidified with 1N HCl and extracted with Et₂O(2×100 ml). the combined organic layers were washed with sat'd NaCl,dried (Na₂SO₄), filtered and evaporated to give the product (590 mg)that was used without further purification.

Preparation 13

Step 1:

To a stirred, ice-cold mixture of (S)-Boc-3,5-difluorophenylalanine(20.00 g, 66.4 mmol) in MeOH (50 ml) and toluene (250 ml) was added(trimethylsilyl)diazo-methane (53 ml, 106 mmol, 2.0 M in hexane) inportions. After the addition, the reaction was stirred for about 0.5 h,quenched with glacial AcOH (1 ml) and concentrated in vacuo. The residuewas used directly in the next step. The residue was dissolved inanhydrous THF (200 ml), cooled to 0° C., and LiAlH₄ (2.52 g, 66.4 mmol)was added in portions. After the addition, the reaction was allowed tostir at 0° C. for 20 min then quenched with of 15% aq. NaOH (2.0 ml) andH₂O (8.0 ml). The resulting slurry was filtered, the residue washed withTHF, and the combined filtrate and washings were concentrated in vacuoto give the product as a white solid (17.65 g, 93%). ¹H NMR (CDCl₃) δ6.73 (m, 2H), 6.62 (m, 1H), 4.75 (s, br, 1H), 3.80 (s, br, 1H), 3.61 (m,1H), 3.52 (m, 1H), 2.80 (m, 2H), 1.37 (s, 9H). MS m/e 288 (M+H)⁺.

Step 2:

A flask charged with the product of Step 1 (3.00 g, 10.5 mmol), EtOAc(150 ml) and IBX (8.78 g, 31.4 mmol) was heated to 95° C. and stirredfor 3.5 h. The reaction mixture was allowed to cool to RT, filtered andconcentrated in vacuo to provide the product as white solid (2.98 g,100%). ¹H NMR (CDCl₃) δ 9.59 (s, 1H), 6.65 (m, 3H), 5.03 (m, 1H), 4.35(m, 1H), 3.13 (m, 1H), 3.01 (m, 1H), 1.39 (s, 9H).

Preparation 14

Step 1:

Trimethylsilyldiazomethane (2.0 M Hexanes, 95 ml, 190 mmol) was added toa solution of Boc-(L)-3,5-difluorophenylalanine (40 g, 133 mmol) in MeOH(50 ml) and toluene (250 ml) at 0° C. After 60 min at RT, AcOH was addedto quench the excess trimethylsilyldiazomethane, and the reactionmixture was concentrated under vacuum to give the methyl ester inquantitative yield (42.3 g). 4 M HCl/dioxane (150 ml, 600 mmol) wasadded to a solution of the methyl ester (42.3 g) in 20% MeOH/CH₂Cl₂ (130ml) at 0° C., and the reaction was stirred for 4 h at RT. The reactionwas concentrated under vacuum to give the product HCl salt (33.4 g,quantitative). LCMS (Conditions A): t_(R)=2.62 min; 431 (2M+H)⁺, 216(M+H)⁺.

Step 2:

NaHCO₃ (55.9 g, 665 mmol) and BnBr (68.2 g, 399 mmol) were added to asolution of the product of Step 1 (33.4 g, 133 mmol) in THF (600 ml) andDMSO (150 ml) at RT. The reaction mixture was stirred for 24 h at 70°C., then cooled to RT and diluted with water (400 ml). After stirringfor 1 h at RT, the layers were separated and the aqueous layer extractedwith EtOAc (3×). The combined organic layers were washed (NaHCO₃), dried(MgSO₄) and concentrated, and the residue chromatographed (SiO₂, 0% to30% EtOAc/Hexanes) to give the intermediate N,N-dibenzylated methylester (39.4 g, 75%). LCMS (Conditions A) t_(R)=5.90 min; 396 (M+H)⁺.

LiAlH₄ (6.49 g, 171 mmol) was added to a solution of the methyl ester(45.0 g, 114 mmol) in THF (500 ml) at 0° C. After the addition wascompleted, the reaction mixture was stirred at RT for 5 h, then quenchedwith water (5 ml), 15% NaOH (10 ml) and an additional amount of water (7ml). After vigorously stirring the suspension, the mixture was filtered,and the filtrate concentrated. The resulting residue was chromatographed(SiO₂, 0% to 50% EtOAc/Hexanes) to give the product (34.8 g, 71%). LCMS(Conditions A) t_(R)=4.53 min; 368 (M+H)⁺.

Step 3:

DMSO (4.45 ml, 62.7 mmol) in CH₂Cl₂ (10 ml) was added to a solution ofoxalylchloride (2.70 ml, 31.3 mmol) in CH₂Cl₂ (60 ml) at −78° C. After10 min, a solution of the product of Step 2 (10.0 g, 27.2 mmol) inCH₂Cl₂ (40 ml) was added. The reaction mixture was stirred for 90 min at−78 DC, followed by addition of DIEA (18.8 ml, 108 mmol). The reactionmixture was stirred for 2 h at RT, then quenched with water. The aqueouslayer was extracted with CH₂Cl₂, and the combined organic layers washed(2× water, 2×NH₄Cl, 1× brine), dried (MgSO₄), and concentrated to givethe product (10.32 g, >theoretical yield). ¹H NMR (400 MHz, CDCl₃)

=9.72 (s, 1H), 7.33-7.24 (m, 10H), 6.65-6.61 (m, 3H), 3.82 (d, J=13.6Hz, 2H), 3.68 (d, J=14 Hz, 2H), 3.51 (m, 1H), 3.10 (m, 1H), 2.86 (m,1H).

Preparation 15

Step 1.

L-Leucinol (5.27 g, 45.0 mmol) was added to a stirred solution ofpotassium carbonate (17.76 g, 128.5 mmol) in water (25 ml) at RT and themixture was heated to 65° C. A solution of benzyl bromide (15.44 g,90.27 mmol) in EtOH (12 ml) was added and the mixture was stirred at 65°C. for 1 h. The mixture was diluted with CH₂Cl₂ (50 ml) and water (25ml), the aqueous layer was extracted with CH₂Cl₂ (50 ml) and thecombined organic layers were dried (MgSO₄), concentrated, and purifiedby column chromatography (SiO₂, gradient EtOAc/Hexanes 0-8%) to give theproduct (12.63 g, 94%). MS m/e 298 (M+H)⁺.

Step 2:

The product of Step 1 was converted to the aldehyde by essentially theprocedure of Preparation 14, Step 3, and was used directly.

Preparation 16

Step 1:

A mixture of (S)-2-t-butoxycarbonylamino-3-cyclohexyl-1-propanol (4.00g, 15.5 mmol) in CH₂Cl₂ (10 ml) and 4N HCl in dioxane (10 ml) wasstirred at RT for 16 h. The mixture was diluted with CH₂Cl₂ (40 ml) andwashed with aqueous NH₄OH (30 ml). The aqueous layer was extracted withCH₂Cl₂ (40 ml) and the combined organic layer was dried (MgSO₄) andconcentrated to give the product (2.78 g, 100%). MS m/e 158 (M+H)⁺.

Step 2

The product of Step 1 was dibenzylated in analogy to the procedure ofPreparation 15, Step 1. The dibenzylated product was converted to theproduct aldehyde in analogy to the procedure of Preparation 14, Step 3.

Example 1

Step 1:

In analogy to the literature procedure (Pettit et al. Synthesis (1996),719-725), NEt₃ (2.0 ml, 14.44 mmol) was added to a solution ofPreparation 1 (3.31 g, 11.16 mmol) in CH₂Cl₂ (46 ml) at 0° C., followedby dropwise addition of Bu₂BOTf (1.0 M in CH₂Cl₂, 12.0 ml, 12 mmol).After 45 min at 0° C., the yellow solution was cooled to −78° C., and asolution of N-(tert-butoxycarbonyl)-D-prolinal (2.46 g, 12.34 mmol) inCH₂Cl₂ (5 ml) was added. The reaction was stirred for 1 h at −78° C., 2h at 0° C. and 1 h at 23° C., and was quenched with MeOH (75ml)-phosphate buffer (pH 7.0, 25 ml). After cooling the solution to −10°C., a solution of H₂O₂ (30% in water, 25 ml)-MeOH (50 ml) was added suchthat the internal temperature remained below 4° C. After stirring for 60min at 23° C., the volatiles were removed in vacuo, and the aqueousresidue was extracted with Et₂O (3×), dried (Na₂SO₄) and concentratedunder reduced pressure. Purification of the residue by chromatography(SiO₂, 20→30% EtOAc/hexanes) gave the product (3.03 g, 61%) along withrecovered imide (1.98 g, 6.66 mmol). ¹H NMR (400 MHz, CDCl₃) δ 6.83 (m,2H), 6.51 (m, 1H), 4.57 (m, 1H), 4.33 (m, 1H), 3.94-4.15 (m, 3H), 3.80(m, 1H), 3.23-3.39 (m, 4H), 2.99 (t, 1H, J=12.8 Hz), 1.98 (m, 1H), 1.97(m, 1H), 1.76 (m, 3H), 1.48 (s, 9H), 0.73 (d, 3H, J=6.8 Hz), 0.29 (d,3H, J=6.8 Hz); LCMS (Conditions A): t_(R)=4.65 min, 497 (M+H)⁺, 441(M-Bu+H)⁺, 397 (M-Boc+H)⁺.

Step 2:

To a solution of the product of Step 1 (3.91 g, 7.89 mmol) in THF (45ml) and water (11 ml) at 0° C. was added H₂O₂ (30% in water, 3.9 ml),followed by an aqueous solution of LiOH (378 mg, 15.78 mmol in 24 mlwater, sonicated to completely dissolve LiOH). After 18 h at 0° C., thereaction was quenched with saturated aqueous Na₂SO₃ and stirred at 23°C. for 2 h. After removal of all volatiles, the residue was diluted withNaHCO₃, extracted with CH₂Cl₂ (3×), acidified to pH 2 (1N HCl), saltedout with NaCl (s) and extracted with Et₂O (3×). The combined organiclayers were washed with water (1×) and brine (1×), dried (Na₂SO₄) andconcentrated in vacuo to yield the product (2.24 g, 5.80 mmol, 74%); ¹HNMR (400 MHz, CDCl₃) δ 6.71 (m, 2H), 6.57 (m, 1H), 4.09 (m, 1H), 3.90(m, 1H), 3.49 (m, 1H), 3.10-3.23 (m, 2H), 2.86 (m, 1H), 2.64 (m, 1H),1.47-2.00 (m, 4H), 1.48 (s, 9H); LCMS (Conditions A): t_(R)=3.93 min,386 (M+H)⁺, 330 (M-Bu+H)⁺, 286 (M-Boc+H)⁺.

Step 3:

To a solution of the product of Step 2 (2.23 g, 5.80 mmol) in DMF (20ml) at −78° C. was added NaH (60%, 510 mg, 12.75 mmol), followed bybenzyl bromide (810 μl, 6.81 mmol). The reaction was warmed to 23° C.over 18 h. The volatiles were removed in vacuo, and the residue wastaken up in water-Et₂O. The aqueous layer was extracted with Et₂O (2×),adjusted to pH 3 (1 M HCl), extracted with EtOAc (3×), and the combinedorganic layers were dried (MgSO₄) and concentrated under reducedpressure. Purification of the residue by chromatography (SiO₂, 10→50%EtOAc/hexanes containing 1% AcOH) gave recovered starting material (372mg, 0.97 mmol) and the product (616 mg, 22%); ¹H NMR (400 MHz, CDCl₃,complicated by the presence of rotamers) δ 8.0-9.0 (bs, 1H), 7.21 (m,5H), 6.68 (m, 2H), 6.60 (m, 1H), 4.50-4.64 (m, 2H), 3.60-3.83 (m, 1H),3.37-3.60 (m, 2H), 3.07-3.24 (m, 2H), 2.82 (m, 1H), 2.60 (m, 1H),1.96-2.08 (m, 1H), 1.79-1.96 (m, 2H), 1.66 (m, 1H), 1.40 (m, 9H); MS 498(M+Na)⁺, 420 (M-Bu+H)⁺, 376 (M-Boc+H)⁺.

Step 4:

NEt₃ (155 μL, 1.12 mmol) and DPPA (145 μL, 0.67 mmol) were added to theproduct of Step 3 (265 mg, 0.56 mmol) in toluene (3 ml) at 23° C. After3 h at 95° C., BnOH (240 μl, 2.24 mmol) was added, followed by stirringat 80° C. for 18 h. After removing the volatiles in vacuo, the residuewas purified by chromatography (SiO₂, 5→10% EtOAc/hexanes) andnormal-phase HPLC (1→10% iPrOH/hexanes) to give the product (103 mg,32%). ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.30 (m, 10H), 6.57-6.70 (m, 3H),5.30 (m, 1 NH), 4.85-5.05 (m, 2H), 4.40-4.56 (m, 2H), 4.05 (m, 1H),3.65-3.95 (m, 2H), 3.00-3.60 (m, 3H), 2.40-2.60 (m, 1H), 2.05 (m, 1H),1.55-1.95 (m, 3H), 1.41 (s, 9H); LCMS (Conditions A): t_(R)=5.18 min,581 (M+H)⁺, 525 (M−Bu+H)⁺, 481 (M-Boc+H)⁺.

Step 5:

A solution of the product of Step 4 (100 mg, 172 μmol) in MeOH (4 ml)was hydrogenated over 20% Pd(OH)₂/C (40 mg) at 1 atm of H₂ pressure for18 h. The mixture was filtered and concentrated under reduced pressureto yield the product (61 mg, 100%) which was used without furtherpurification in the next step.

Step 6:

To EDC-resin (60 mg, 84 mmol at 1.45 mmol/g loading) was added asolution of the product of Step 5 (10 mg, 28 mmol in 500 μl ofTHF/CH₃CN/DMF, 2:2:1 v/v/v), followed by a solution of HOBt (5.7 mg, 42μmol in 200 μl THF) and a solution of Preparation 2A (6.6 mg, 34 mmol in700 μl THF/CH₃CN, 1:1 v/v). After gently shaking the reaction for 18 hat 23° C., PS-trisamine resin (39 mg, 170 μmol at 4.36 mmol/g loading)and PS-NCO resin (58 mg, 85 mmol at 1.47 mmol/g loading) was added.After 6 h of further shaking, the reaction was filtered, the resinwashed with THF (2×1 ml), and the volatiles removed under vacuum. Theproduct was deprotected using 20% TFA/CH₂Cl₂ (3 ml) for 6 h at 23° C.,followed by removal of volatiles under vacuum. The resulting residue wasexposed to 1 M HCl/MeOH (300 μl) for 30 min at 23° C., then concentratedunder vacuum to give the product (7.7 mg, 17 μmol, 60%). ¹H NMR (400MHz, CD₃OD) δ 6.70-6.84 (m, 3H), 3.99 (m, 1H), 3.81-3.88 (m, 1H),3.60-3.68 (m, 2H), 3.48 (m, 1H), 3.43 (m, 1H), 3.03-3.15 (m, 2H), 2.79(m, 1H), 2.38-2.66 (m, 2H), 1.90-2.08 (m, 5H), 1.15-1.44 (m, 7H), 0.87(m, 3H, J=7.6 Hz); LCMS (Conditions A) t_(R)=3.42 min (isomer 1) andt_(R)=3.63 min (isomer 2), 424 (M+H), 406 (M−H₂O+H).

By essentially the same procedure set forth in Example 1, substitutingPreparations 2Q and 4, Examples 1B and 1C were prepared.

Example 1B

¹H NMR δ 7.12-7.30 (m, 5H), 6.79 (m, 3H), 6.55 (m, 1H), 4.37 (m, 1H),4.30 (m, 1H), 3.90-4.00 (m, 1H), 3.80-3.85 (m, 1H), 3.63 (m, 1H),3.54-3.60 (m, 1H), 3.44 (m, 1H), 3.03 (m, 1H), 2.44-2.70 (m, 5H),1.80-2.11 (m, 6H). Isomer 1: LCMS (Conditions A): t_(R)=3.58 min; 458(M+H). Isomer 2: LCMS (Conditions A): t_(R)=3.74 min; 458 (M+H).

Example 1C

¹H NMR δ=6.70-6.80 (m, 3H), 4.78 (m, 1H), 4.07 (m, 1H), 3.91 (m, 1H),3.66-3.72 (m, 2H), 3.15-3.24 (m, 3H), 3.00-3.05 (m, 2H), 2.64 (m, 1H),1.80-2.09 (m, 5H), 1.49 (m, 1H), 1.39 (m, 2H), 1.20-1.33 (m, 4H), 0.90(t, 3H, J=7.2 Hz). LCMS (Conditions A): t_(R)=3.81 min; 426 (M+H).

Example 1D

Step 1:

A mixture of Preparation 3A (30 mg, 0.14 mmol), Example 1, Step 5 (46mg, 0.13 mmol), HOBt (18 mg, 0.13 mmol), EDCl (25 mg, 0.13 mmol), andEt₃N (19 μl, 0.14 mmol) in CH₂Cl₂ (5 ml) was stirred at RT for 16 h. Themixture was diluted with CH₂Cl₂ (50 ml) and washed with 0.5N NaOH (30ml). The organic layer was dried (MgSO₄), concentrated, and purified byPTLC (1:20 MeOH/CH₂Cl₂) to give the desired product (33 mg, 46%). MS m/e574 (M+Na)⁺.

Step 2:

A solution of the product of Step 1 (33 mg, 0.060 mmol) and TFA (1 ml)in CH₂Cl₂ (5 ml) was stirred in an ice-water bath for 30 min then at RTfor 4 h. The mixture was diluted with CH₂Cl₂ (40 ml) and washed with 5NNH₄OH (10 ml). The organic layer was dried (MgSO₄), concentrated, andpurified by PTLC (15% 2M NH₃/MeOH-85% CH₂Cl₂) to give isomer 1 (5.5 mg,20%) and isomer 2 (13 mg, 48%). Isomer 1: ¹H NMR (400 MHz, CDCl₃) δ 6.97(m, 1H), 6.71 (m, 2H), 6.61 (m, 1H), 4.11 (m, 1H), 3.88 (m, 1H), 3.51(m, 1H), 3.38 (m, 1H), 3.05-3.30 (m, 6H), 2.87 (m, 1H), 2.60 (m, 1H),2.50 (m, 1H), 1.80-2.10 (m, 4H), 1.55 (m, 1H), 1.15-1.50 (m, 6H), 0.85(m, 3H), 0.74 (m, 3H). MS m/e 452 (M+H)⁺. Isomer 2: ¹H NMR (400 MHz,CDCl₃) δ 6.55-6.80 (m, 4H), 3.80-4.30 (m, 3H), 3.61 (m, 1H), 2.45-3.35(m, 11H), 1.60-1.90 (m, 5H), 1.15-1.45 (m, 5H), 0.85 (m, 6H). MS m/e 452(M+H)⁺.

Example 2A

Step 1:

To a solution of N-Boc-D-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid (2.60 g, 9.38 mmol) in toluene/MeOH (5/1, 50 ml) added(trimethylsilyl)diazomethane (2 M in hexanes) until bright yellow colorpersisted in the reaction. The reaction was stirred for 5 min, then AcOHwas added dropwise until the yellow color faded completely. The solutionwas concentrated, and this crude product was used without purification.

To a 0° C. solution of a portion of the above material (2.30 g, 7.90mmol) was added LiAlH₄ (600 mg, 15.8 mmol) as a solid in two portions.The reaction was allowed to warm to RT overnight. After 18 h, thereaction was quenched by slow addition of water (1 ml), followed by aq.NaOH (1.5 ml, 25% w/v), and finally more water (2 ml). The resultingmixture was stirred vigorously for 1 h, then filtered and concentrated.The crude residue was purified by column chromatography (silica, 0→65%EtOAc/hexanes) to give the desired product (500 mg, 1.89 mmol, 24%).LCMS (Conditions A): t_(R)=4.2 min; (M+H)⁺=264.

To a −78° C. solution of oxalyl chloride (215 μl, 318 mg, 2.51 mmol) inCH₂Cl₂ (5.5 ml) was added DMSO (222 μl, 245 mg, 3.13 mmol). After 5 min,a −78° C. solution of the product of the previous step (550 mg, 2.09mmol) in CH₂Cl₂ (5 ml) was added via cannula. After 40 min at −78° C.,DIEA (1.1 ml, 810 mg, 6.3 mmol) was added all at once, and the coolingbath was removed from the reaction. After 10 min, the mixture wasdiluted with water and additional CH₂Cl₂. The phases were separated, andthe aqueous phase was extracted once with CH₂Cl₂. The organic portionswere combined, washed with brine, dried over MgSO₄, filtered, andconcentrated. The crude product was used in subsequent steps withoutfurther purification.

Step 2:

To a −20° C. solution of the product of Preparation 1 (745 mg, 2.51mmol) in CH₂Cl₂ (10.5 ml) was added Et₃N (0.43 ml, 320 mg, 3.1 mmol).After 5 min, di-n-butylboron triflate (1 M in CH₂Cl₂, 2.72 ml, 2.72mmol) was added via syringe over 2 min. The reaction was transferred toan ice/brine bath, stirred for 2 h, and then cooled to −78° C. A 0° C.solution of the product of the Step 1 (assumed 2.09 mmol) in CH₂Cl₂ (3ml) was added dropwise via cannula over 5 min, followed by a CH₂Cl₂rinse (1 ml). This mixture was warmed stepwise to RT as follows: 1.5 hat −78° C., 1.0 h at 0° C., 1.0 h at RT. The reaction mixture was thenquenched by addition of pH 7 phosphate buffer (˜10 ml) and MeOH (˜10ml). The resulting mixture was cooled in an ice/brine bath, and asolution of 35% H₂O₂/MeOH (1/2, 15 ml) was added slowly, such that theinternal temperature of the reaction remained <5° C. After thisaddition, the mixture was warmed to RT and stirred for 45 min. Themixture was further diluted with MeOH and water, then partiallyconcentrated. The mixture was diluted with EtOAc and brine. The phaseswere separated, and the aqueous portion was extracted with EtOAc (4×).The combined organic fractions were washed with sat. aq. NaHCO₃ andbrine, then dried over MgSO₄, filtered, and concentrated. The crudematerial was purified by column chromatography (silica, 0→75%EtOAc/hexanes) to give the desired product (668 mg, 1.20 mmol, 57%).LCMS (Conditions A): t_(R)=5.3 min; (M+H)⁺=559.

Step 3:

To a 0° C. solution of the product of Step 2 (610 mg, 1.09 mmol) inTHF/water (5/1, 6 ml) was added 35% aq. H₂O₂ (0.44 ml) followed by asuspension of LiOH (77 mg, 1.8 mmol) in water (2 ml) that had beensonicated for 10 min. The reaction was stirred at 0° C. for 8 h, thendiluted with an aq. Na₂SO₃ solution (1 g in 5 ml water) and let warm toRT overnight. The mixture was diluted with 1N HCl and CH₂Cl₂. The phaseswere separated and the aqueous extracted with CH₂Cl₂ (3×). The combinedorganic fractions were washed with brine, dried over MgSO₄, filtered,and concentrated. The crude residue was purified by columnchromatography (silica, 0→100% EtOAc/hexanes) to give the desiredcompound (305 mg, 0.682 mmol, 63%). LCMS (Conditions A): t_(R)=4.5 min;(M+H)⁺=448.

Step 4:

To a suspension of the product of Step 3 (305 mg, 0.682 mmol) in toluene(3.5 ml) was added Et₃N (0.19 ml, 140 mg, 1.4 mmol), followed by DPPA(0.18 ml, 225 mg, 0.82 mmol). The mixture became homogeneous. After fivemin, the mixture was heated to 80° C. in a pre-heated oil bath. After 4h, the mixture was cooled to RT and concentrated directly withoutworkup. This crude material was purified by column chromatography(silica, 0→100% EtOAc/hexanes) to give the desired product (300 mg, 0.68mmol, 99%). LCMS (conditions A): t_(R)=4.9 min; (M+H)⁺=445.

Step 5:

To a solution of the product of Step 4 (180 mg, 0.405 mmol) in ethanol(2 ml) was added 1 N aq. LiOH (2.0 ml, 2.0 mmol) The resulting mixturewas heated to 85° C. After 4 h, the reaction mixture was cooled to RTand diluted with water and EtOAc. The phases were separated and theaqueous fraction was extracted with EtOAc (4×). The organic portionswere combined, washed with brine, dried (MgSO₄), filtered, andconcentrated. The crude residue was purified by HPLC (Conditions B) togive the product (138 mg, 0.297 mmol, 73%). LCMS (Conditions A):t_(R)=4.6 min; (M+H)⁺=419.

Step 6:

Reaction of the product of Step 5 (26 mg, 0.056 mmol) with Preparation3A (13 mg, 0.059 mmol) by essentially the procedure set forth in Example1D, Step 1, except that DMF was used in place of CH₂Cl₂, afforded thecrude coupled product. The crude product was purified by HPLC(Conditions B) to give the desired couple product (17 mg, 0.028 mmol,49%), as a 1:1 mixture of diastereomers. To a solution of the abovematerial (14 mg, 0.023 mmol) in CH₂Cl₂ (1 ml) was added 4 N HCl/dioxane(1 ml). After 2 h, the reaction mixture was concentrated. This cruderesidue was purified by HPLC (Conditions C) to give the desiredcompound, a 1:1 mixture of diastereomers. LCMS (Conditions A): t_(R)=4.0min; (M+H)⁺=514; ¹H NMR (CD₃OD, 300 MHz) δ 7.23 (m, 8H), 6.90 (m, 4H),6.81 (m, 2H), 4.52-4.24 (m, 6H), 4.02 (br t, J=9.0 Hz, 2H), 3.54 (m,2H), 3.38 (m, 3H), 3.32-3.05 (m, 9H), 2.67 (m, 5H), 2.54 (m, 1H), 2.28(dt, J_(d)=4.8 Hz, J_(t)=7.2 Hz, 1H), 1.61 (m, 1H), 1.48-1.33 (m, 6H),1.30-1.14 (m, 6H), 0.92 (t, J=7.2 Hz, 3H), 0.85 (t, J=7.2 Hz, 3H), 0.68(t, J=7.5 Hz, 3H), 0.55 (t, J=7.5 Hz, 3H).

Example 2B

Using Preparation 4 and the compound of Example 2A, Step 5, the abovecompound was prepared. ¹H NMR (CD₃OD, 300 MHz) δ 7.22 (m, 4H), 6.88-6.76(m, 3H), 4.80 (dd, J=9.9, 5.7 Hz, 1H), 4.48 (d, J=15.6 Hz, 1H), 4.31 (m,2H), 4.07 (br d, J=10.5 Hz, 1H), 3.68 (m, 2H), 3.39 (dd, J=13.8, 3.0 Hz,1H), 3.26-3.02 (m, 4H), 2.72 (dd, J=13.8, 11.1 Hz, 1H), 1.42 (m, 2H),1.26 (m, 2H), 0.92 (t, J=7.2 Hz). MS m/e 488 (M+H)⁺.

Using the procedures set forth in Example 2A, Steps 1-6, substitutingN-Boc-D-pipecolic acid forN-Boc-D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, the followingexamples were obtained.

Example 3A

Isomer 1; ¹H NMR (CDCl₃, 400 MHz) δ 8.20 (m, 1H), 6.80 (m, 3H), 4.10 (m,1H), 3.69 (m, 1H), 3.48 (m, 1H), 3.40-2.95 (m, 6H), 2.62 (m, 2H), 2.32(m, 1H), 2.15-1.20 (m, 13H), 0.87 (m, 3H), 0.70 (m, 3H). MS m/e 466(M+H)⁺. Isomer 2; ¹H NMR (CDCl₃) δ 8.22 (m, 1H), 6.81 (m, 3H), 4.10 (m,1H), 3.70 (m, 1H), 3.40-2.90 (m, 7H), 2.80-2.50 (m, 4H), 2.10-1.15 (m,12H), 0.88 (m, 6H). MS m/e 466 (M+H)⁺.

Example 3B

¹H NMR (CDCl₃, 400 MHz) δ 8.15 (m, 1H), 6.79 (m, 3H), 4.83 (m, 2H), 4.12(m, 1H), 3.72 (m, 2H), 3.38-2.95 (m, 6H), 2.63 (m, 1H), 2.10-1.20 (m,10H), 0.92 (m, 3H). MS m/e 440 (M+H)⁺.

Example 4A

Step 1:

A solution of N,N-dimethylaminoethanol (2.60 ml, 26.2 mmol) in anhydroushexane (50 ml) was cooled to −5° C. with stirring, to which nBuLi (2.5M/hexane, 21.0 ml, 52.3 mmol) was added slowly. After the addition, thereaction mixture was warmed to 0° C. and stirred for 0.5 h. The reactionmixture was then cooled to −78° C., and 4-chloropyridine (3.00 g, 26.2mmol) in anhydrous hexane (10 ml) was added slowly. The reaction mixturewas stirred at −78° C. for 1.5 h, then a solution of Preparation 14(7.97 g, 21.8 mmol) in anhydrous THF (20 ml) was added dropwise. Afterthe addition, the reaction was allowed to warm to 0° C. and stirred at0° C. for an additional 0.5 h. The reaction mixture was then poured intocold H₂O and extracted with CH₂Cl₂ (3×). The combined organic layerswere dried over Na₂SO₄. The concentrated residue was purified bychromatography over silica gel (EtOAc/Hexane, 0%→25%) to afford theproduct as a light brown oil (4.45 g, 43%). ¹H NMR (CDCl₃, 400 MHz) δ8.31 (d, J=2.8 Hz, 1H), 7.40-7.05 (m, 11H), 6.87 (d, J=16 Hz, 1H), 6.55(m, 1H), 6.35 (m, 2H), 5.15 (s, br, 1H), 4.51 (s, br, 1H), 3.95 (d,J=14.0 Hz, 2H), 3.68 (d, J=14 Hz, 1H), 3.14 (m, 1H), 2.93 (m, 1H), 2.45(m, 1H). MS (M+H)⁺=479 (M+H)⁺.

Step 2:

To a solution of the product of Step 1 (1.11 g, 2.32 mmol) in absoluteethanol (50 ml), sodium ethoxide (473 mg, 6.95 mmol) was added. Thereaction mixture was heated to reflux for 3 h, then additional EtONa(315 mg, 4.63 mmol) was added. The mixture was refluxed for 19 h, thentransferred to a glass pressure tube and additional EtONa (473 mg, 6.95mmol) was added. The mixture was heated at 120° C. for 22 h and then150° C. for 8 h. After the mixture had cooled to RT, it was poured tosaturated NH₄Cl and extracted with CH₂Cl₂ (3×). The combined organiclayers were dried over Na₂SO₄. The concentrated residue was separated byPTLC (EtOAc/hexane, 1:4) to afford the product (0.75 g, 66%). ¹H NMR(CDCl₃, 400 MHz) δ 8.21 (d, J=6.0 Hz, 1H), 7.40-7.05 (m, 10H), 6.62 (m,1H), 6.58 (m, 1H), 6.31 (m, 2H), 6.20 (d, J=2.0 Hz, 1H), 5.19 (s, 1H),4.06 (d, J=14.4 Hz, 2H), 3.90 (m, 1H), 3.78 (m, 1H), 3.69 (d, J=14.4 Hz,2H), 3.10 (m, 1H), 2.92 (m, 1H), 2.35 (m, 1H), 1.35 (t, J=6.8, 3H). MSm/e 489 (M+H)⁺.

Step 3:

The product of Step 2 (161 mg, 0.330 mmol), 20% Pd(OH)₂/C (161 mg), andAcOH (0.1 ml) in MeOH (10 ml) was stirred under 1 atm H₂ for 3 h at RTthen filtered through celite. The concentrated residue was separated byPTLC (7M NH₃/MeOH: CH₂Cl₂, 1:10) to give the product (73.2 mg, 72%). ¹HNMR (CDCl₃, 400 MHz) δ 8.30 (d, J=5.6 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H),6.69 (m, 1H), 6.63 (m, 2H), 6.58 (m, 1H), 4.66 (d, 1H), 4.05 (q, J=6.8Hz, 2H), 3.38 (m, 1H), 2.63 (m, 1H), 2.38 (m, 1H), 1.40 (t, J=7.2 Hz,3H). MS m/e 309 (M+H)⁺.

Step 4:

Reaction of the product of Step 3 with Preparation 3A by essentially theprocedure set forth in Example 1D, Step 1 gave the separateddiastereomeric products.

Isomer 1 (higher Rf): ¹H NMR (CDCl₃, 400 MHz) δ 8.28 (d, J=5.6 Hz, 1H),6.74 (s, 1H), 6.70 (m, 1H), 7.51 (m, 3H), 6.35 (m, 1H), 4.81 (d, J=2.8Hz, 1H), 4.54 (m, 1H), 4.02 (m, 2H), 3.37 (m, 2H), 3.21 (m, 2H),2.70-2.45 (m, 3H), 2.39 (M, 1H), 1.59 (m, 1H), 1.50-1.20 (m, 8H), 0.87(t, J=8.6 Hz, 3H), 0.73 (t, J=8.6 Hz). MS m/e 504 (M+H)⁺.

Isomer 2 (lower Rf): ¹H NMR (CDCl₃, 400 MHz) δ 8.29 (d, J=5.6 Hz, 1H),6.73 (m, 2H), 6.52 (m, 3H), 6.31 (m, 1H), 4.79 (m, 1H), 4.55 (m, 1H),4.02 (m, 2H), 3.30-3.05 (m, 4H), 2.75-2.50 (m, 3H), 2.41 (m, 1H), 1.81(m, 1H), 1.70-1.20 (m, 8H), 0.89 (m, 6H). MS m/e 504 (M+H)⁺.

Step 5

A mixture of the product of Step 4 (Isomer 1, 17.0 mg, 0.034 mmol), PtO₂(17.0 mg) and acetic acid (5 ml) was stirred under hydrogen balloon for24 h and filtered through celite. The concentrated residue was separatedby HPLC(C-18, 25 ml/min, 10→95% MeCN/H₂O with 0.1% HCO₂H) to afford theproduct as a formate salt. LCMS (conditions A) t_(R)=2.71 min, m/e 510(M+H)⁺.

Using the appropriate starting materials and essentially the sameprocedure the following compounds were prepared:

LCMS Example Preparation Structure (conditions A) 4B

t_(R) = 2.63 min m/e = 512 (M + H)⁺ 4C

t_(R) = 3.02 min m/e = 496 (M + H)⁺

Example 5A

Step 1:

Piperazin-2-one (1 g, 10 mmol) was dissolved in CH₂Cl₂ (40 ml), andBoc₂O (2.4 g, 11 mmol, 1.1 eq), Et₃N (2.02 g, 20 mmol, 2 eq) and DMAP(0.024 g, 0.2 mmol, 2 mol %) were added. After the mixture was stirredat RT for 16 h, it was acidified with 1N HCl. The organic layer wasseparated, washed with saturated NaHCO₃, brine, dried (Na₂SO₄), andconcentrated in vacuo to give the product (1.8 g, 90%) as a white solid.¹H NMR (CDCl₃, 300 MHz) δ 6.70 (1H, bs), 4.08 (2H, s), 3.62 (2H, t,J=6.0 Hz), 3.37 (2H, m), 1.46 (9H, s).

Step 2:

To a solution of the product of Step 1 (1.17 g, 5.87 mmol) in DMF (25ml) at RT was added NaH (60% dispersion in mineral oil, 352 mg, 8.8mmol, 1.5 eq) and the resulting mixture was stirred at RT for 2 h.Benzyl bromide (0.84 ml, 7.04 mmol, 1.2 eq) was added and the reactionwas heated at 70° C. for 16 h. The reaction mixture was cooled to RT andthe excess NaH was quenched carefully by the dropwise addition of MeOH.The solvent was evaporated in vacuo and the residue was chromatographed(SiO₂, 70% EtOAc/hexanes) to give the product (1.6 g, 95%) as a whitesolid. ¹H NMR (CDCl₃, 300 MHz) δ 7.28 (5H, m), 4.62 (2H, s), 4.16 (2H,s), 3.58 (2H, m, J=5.1 Hz), 3.25 (2H, m, J=5.4 Hz), 1.46 (9H, s).

Step 3:

To a solution of diisopropylamine (3.712 g, 36.68 mmol) in anhydrous THF(20 ml) at −78° C. was added 2.5 M BuLi in hexanes (14.2 ml, 35.5 mmol).After 5 min, the solution was placed in an ice-water bath and stirredfor 30 min. The mixture was cooled to −78° C. again and a solution ofthe product of Step 2 (8.875 g, 30.57 mmol) in THF (30 ml) was added andthe mixture was stirred for 1.5 h at −78° C. A solution of Preparation14 (12.1 g, 33.11 mmol) in THF (20 ml) was added and the resultingmixture was allowed to warm to RT overnight. The mixture was partitionedbetween ether (150 ml) and water (200 ml). The aqueous layer wasextracted with ether (3×150 ml). The combined organic layers were dried(MgSO₄), concentrated, and purified by column chromatography (SiO₂,gradient 0-20% EtOAc/Hexanes) to give a light yellow solid (9.00 g,41%). MS m/e 656 (M+H)⁺.

Step 4:

A mixture of the product of Step 3 (495 mg, 0.755 mmol), 20% Pd(OH)₂/C(493 mg), and a catalytic amount of acetic acid in EtOH (15 ml) wasstirred under H₂ (1 atm) for 5 h at RT. The mixture was filtered througha pad of Celite and concentrated. The residue was dissolved in CH₂Cl₂(50 ml) and washed with aq. NH₄OH (15 ml). The organic layer was dried(MgSO₄) and concentrated to give the product (326 mg, 91%). MS m/e 476(M+H)⁺.

Step 5:

A mixture of the product of Step 4 (56 mg, 0.12 mmol), Preparation 2JJ(24 mg, 0.14 mmol), HOBt (19 mg, 0.14 mmol), EDCl (54 mg, 0.28 mmol),and triethylamine (57 mg, 0.57 mmol) in CH₂Cl₂ (5 ml) was stirred at RTfor 17 h. The mixture was diluted with CH₂Cl₂ (50 ml), washed with 5%citric acid and saturated sodium bicarbonate, dried (MgSO₄),concentrated, and purified by PTLC (5% MeOH/CH₂Cl₂) to give the product(65 mg, 86%). MS m/e 627 (M+H)⁺.

Step 6:

A solution of the product of Step 5 (15 mg, 0.024 mmol) and TFA (0.4 ml)in CH₂Cl₂ (3 ml) was stirred at RT for 1.5 h. The mixture wasconcentrated and purified by PTLC (5% 2M NH₃/MeOH-95% CH₂Cl₂) to givethe product (11 mg, 89%). ¹H NMR (CDCl₃) δ 7.15-7.35 (m, 5H), 6.72 (m,2H), 6.61 (m, 1H), 6.42 (b, 1H), 5.64 (m, 1H), 5.31 (b, 1H), 5.14 (m,2H), 4.62 (d, 1H, J=14.8 Hz), 4.51 (m, 2H), 4.03 (m, 1H), 3.80 (m, 2H),3.50 (m, 1H), 3.37 (m, 3H), 3.15 (m, 2H), 3.02 (m, 1H), 2.92 (m, 3H),2.39 (m, 2H). LCMS (Conditions A): t_(R)=2.74 min; m/e 527 (M+H)⁺.

LCMS Ex. Preparation Example (conditions A) 5B

t_(R) = 2.48 min m/e = 515 (M + H)+ 5C

t_(R) = 3.11 min m/e = 543 (M + H)+ 5D

t_(R) = 3.35 min m/e = 557 (M + H)+ 5E

t_(R) = 3.51 min m/e = 571 (M + H)+ 5F

t_(R) = 2.92 min m/e = 529 (M + H)⁺ t_(R) = 2.90 min m/e = 529 (M + H)⁺5G

t_(R) = 3.06 min; 543 (M + H)⁺ t_(R) = 3.05 min; 543 (M + H)⁺ 5H

t_(R) = 3.06 min; 543 (M + H)⁺ t_(R) = 3.08 min; 543 (M + H)⁺ 5I

t_(R) = 3.35 min; 557 (M + H)⁺ t_(R) = 3.37 min; 557 (M + H)⁺ 5J

t_(R) = 3.51 min; 571 (M + H)⁺ t_(R) = 3.55 min; 571 (M + H)⁺ 5K

t_(R) = 3.01 min; 541 (M + H)⁺ t_(R) = 3.03 min; 541 (M + H)⁺ 5L

t_(R) = 2.70 min; 545 (M + H)⁺ t_(R) = 2.72 min; 545 (M + H)⁺ 5M

t_(R) = 3.65 min; 585 (M + H)⁺ t_(R) = 3.64 min; 585 (M + H)⁺ 5N

t_(R) = 3.28 min; 557 (M + H)⁺ t_(R) = 3.27 min; 557 (M + H)⁺ 5O

t_(R) = 3.07 min; 573 (M + H)⁺ t_(R) = 3.08 min; 573 (M + H)⁺ 5P

t_(R) = 2.85 min; 559 (M + H)⁺ t_(R) = 2.85 min; 559 (M + H)⁺ 5Q

t_(R) = 3.26 min; 577 (M + H)⁺ t_(R) = 2.97 min; 577 (M + H)⁺ 5R

t_(R) = 3.35 min; 571 (M + H)⁺ t_(R) = 3.36 min; 571 (M + H)⁺ 5S

t_(R) = 3.34 min; 585 (M + H)⁺ 5T

t_(R) = 3.74 min; 633 (M + H)⁺ 5U

t_(R) = 3.91 min; 647 (M + H)⁺ 5V

t_(R) = 3.81 min; 613 (M + H)⁺ 5W

t_(R) = 2.72 min; 543 (M + H)⁺ t_(R) = 2.71 min; 543 (M + H)⁺ 5X

t_(R) = 2.84 min; 557 (M + H)⁺ 5Y

t_(R) = 2.98 min; 571 (M + H)⁺ t_(R) = 2.97 min; 571 (M + H)⁺ 5Z

t_(R) = 3.07 min; 544 (M + H)⁺ 5AA

t_(R) = 2.83 min; 558 (M + H)⁺ 5BB

t_(R) = 2.94 min; 572 (M + H)⁺ 5CC

t_(R) = 3.20 min; 572 (M + H)⁺ 5DD

t_(R) = 3.33 min; 584 (M + H)⁺ 5EE

t_(R) = 3.10 min; 572 (M + H)⁺ 5FF

t_(R) = 3.91 min; m/e = 648 5GG

t_(R) = 3.20 min; 586 (M + H)⁺ 5HH

t_(R) = 3.12 min; 581 (M + H)⁺ 5II

t_(R) = 2.85 min; 555 (M + H)⁺ 5JJ

t_(R) = 2.58 min: 545 (M + H)⁺ 5KK

t_(R) = 2.08 min: 531 (M + H)⁺

Example 5LL

Step 1:

A mixture of the product of Example 5A, Step 4 (56 mg, 0.12 mmol),Preparation 2JJ (24 mg, 0.14 mmol), were coupled in analogy to theprocedure of Example 5A, Step 5. The crude product was purified by PTLC(5% MeOH/CH₂Cl₂) to give the product (65 mg, 86%). MS m/e 627 (M+H)⁺.

Step 2:

A mixture of the product of Step 1 (50 mg, 0.080 mmol) and 10% Pd/C (20mg) in EtOH (5 ml) was stirred under H₂ (1 atm) for 4 h. The mixture wasfiltered and concentrated to give the product (46 mg, 91%).

Step 3:

A solution of the product of Step 2 (46 mg, 0.073 mmol) and TFA (1 ml)in CH₂Cl₂ (4 ml) was stirred at RT for 1 h. The mixture was concentratedand purified by PTLC (8% 2M NH₃/MeOH—CH₂Cl₂) to give the product (24 mg,62%). ¹H NMR (CDCl₃) δ 7.15-7.35 (m, 5H), 6.72 (m, 2H), 6.60 (m, 1H),6.37 (m, 1H), 4.62 (m, 1H), 4.49 (m, 2H), 3.94 (m, 1H), 2.7-3.5 (m,12H), 2.34 (m, 2H), 1.44 (m, 3H), 0.83 (t, 3H, J=7.2 Hz). LCMS(Conditions A): t_(R)=2.64 min; m/e 529 (M+H)⁺.

Example 5MM

A suspension of Example 5HH (26 mg, 0.045 mmol) and Pd(OH)₂/C (40 mg) inMeOH (8 ml) was stirred under H₂ for 1.5 h. The reaction mixture wasfiltered and the filtrate was evaporated. PTLC of the residue gave theproduct (22 mg, 88%). LCMS (Conditions A) t_(R)=3.54 min; 585 (M+H)⁺.

Example 5NN

Example 5NN was prepared from Example 511 in analogy to Example 5MM.LCMS (conditions A) t_(R)=3.26 min; 557 (M+H)⁺.

Example 6

Preparation 15 was converted to the product in analogy to the procedureof Example 5A, except that Preparation 2LL was used in Step 5 in placeof Preparation 2JJ. LCMS (conditions A) t_(R)=2.83 min; 473 (M+H)⁺.

Example 7

Preparation 16 was converted to the product in analogy to the procedureof Example 5A, except that Preparation 2LL was used in Step 5 in placeof Preparation 2JJ. LCMS (conditions A) t_(R)=2.82 min; 513 (M+H)⁺.

Example 8A

Step 1:

To a solution of the product of Example 5A, Step 3 (1.32 g, 2.01 mmol)in THF (27 ml) was added 2M BH₃—SMe₂ in THF (4.0 ml) and the mixture washeated to 60° C. for 2.5 h. The mixture was treated with saturatedcitric acid (25 ml) and extracted with EtOAc (3×40 ml). The combinedorganic layer was evaporated to dryness and the residue was partitionedbetween CH₂Cl₂ (100 ml) and aqueous NH₄OH (30 ml). The organic layer wasdried (MgSO₄), concentrated, and purified by column chromatography(SiO₂, gradient EtOAc/hexanes 0-20%) to give the product (1.16 g, 90%).MS m/e 642 (M+H)⁺.

Step 2:

A mixture of the product of Step 1 (1.16 g, 1.81 mmol), 20% Pd(OH)₂/C(1.17 g), and catalytic amount of AcOH in EtOH (12 ml) was stirred underH₂ (1 atm) for 16 h. The mixture was filtered through a pad of Celiteand concentrated. The residue was taken up in CH₂Cl₂ (40 ml) and washedwith aqueous NH₄OH (20 ml). The organic layer was dried (MgSO₄) andconcentrated to give the product (611 mg, 91%). MS m/e 372 (M+H)⁺.

Step 3:

To a solution of the product of Step 2 (92 mg, 0.25 mmol) and Et₃N (35μl, 0.25 mmol) in CH₂Cl₂ (5 ml) in an ice-water bath was addedbenzenesulfonyl chloride (43 mg, 0.25 mmol) in CH₂Cl₂ (3 ml) dropwise.The mixture was stirred in ice-water bath for 1.5 h, diluted with CH₂Cl₂(40 ml), and washed with 1N NaOH (30 ml). The organic layer was dried(MgSO₄), concentrated, and purified by PTLC (5% MeOH/CH₂Cl₂) to give theproduct (106 mg, 84%). MS m/e 512 (M+H)⁺.

Step 4:

The product of Step 3 (106 mg, 0.207 mmol) and Preparation 2LL (43 mg,0.23 mmol) were couple in analogy to the procedure of Example 5A Step 5.The crude product was purified by PTLC (3% MeOH/CH₂Cl₂) to give theproduct (52 mg, 37%). MS m/e 701 (M+Na)⁺.

Step 5:

A mixture of the product of Step 4 (52 mg, 0.077 mmol) and TFA (0.9 ml)in CH₂Cl₂ (4 ml) was stirred in an ice-water bath for 30 min then at RTfor 2 h. The mixture was diluted with CH₂Cl₂ (40 ml) and washed withaqueous NH₄OH (20 ml). The organic layer was dried (MgSO₄),concentrated, and purified by PTLC (5% MeOH/CH₂Cl₂) to give the product(37 mg, 83%). ¹H NMR (CDCl₃) δ 7.72 (m, 2H), 7.62 (m, 1H), 7.54 (m, 2H),6.76 (m, 2H), 6.69 (d, 1H, J=8.8 Hz), 6.61 (m, 1H), 4.37 (m, 1H), 3.72(m, 1H), 3.52 (m, 2H), 3.41 (m, 1H), 3.22 (m, 3H), 3.01 (m, 3H), 2.80(m, 3H), 2.51 (m, 3H), 2.31 (m, 1H), 1.43 (m, 2H), 1.24 (m, 2H), 0.89(m, 3H). LCMS (Conditions A): t_(R)=3.09 min; m/e 579 (M+H)⁺.

By essentially the same procedure set forth in Example 8A, the followingexample was prepared.

LCMS Example 8B (Conditions A)

t_(R) = 2.63 min m/e = 517 (M + H)+

Examples 8C-8III

The Examples in the Table below were prepared according to the followingprocedure:

Step 1:

A mixture of the product of Example 10A, Step 1 (969 mg, 2.10 mmol),Preparation 2A (395 mg, 2.14 mmol), EDCl (403 mg, 2.10 mmol), HOBt (299mg, 2.21 mmol), and triethylamine (297 mg, 2.93 mmol) in CH₂Cl₂ (25 ml)was stirred at RT for 16 h. The mixture was diluted with CH₂Cl₂ (50 ml)and washed with 1N NaOH (30 ml). The organic layer was dried (MgSO₄),concentrated, and purified by column chromatography (SiO₂, gradientMeOH/CH₂Cl₂ 0-3%) to give the product (1.25 g, 95%). MS m/e 629 (M+H)⁺.

Step 2:

A mixture of the product of Step 1 (1.19 g, 1.89 mmol) and 20% Pd(OH)₂/C(1.20 g) in EtOH (20 ml) was stirred under H₂ for 4 h. The mixture wasfiltered through a pad of Celite and concentrated. The residue waspartitioned between CH₂Cl₂ (100 ml) and 1N NaOH (20 ml). The organiclayer was dried (MgSO₄) and concentrated to give the product (965 mg,95%). MS m/e 539 (M+H)⁺.

Step 3:

To a mixture of the product of Step 2 (10 mg, 19 mmol) and PS-DIEA (33mg, 124 μmol) in CH₃CN/THF (7:3, 1 ml) was added the sulfonyl chloride(0.5 M in 1,2-dichloroethane, 56 μl, 28 μmol). The mixture was shaken atRT for 16 h and filtered into a well charged with PS-NCO (37 mg, 57mmol) and PS-trisamine (32 mg, 135 μmol). The resulting mixture wasshaken at RT for 24 h and filtered. The filtrate was concentrated andthe residue was dissolved in 20% TFA/CH₂Cl₂ (1 ml). The solution wasshaken at RT for 2.5 h and evaporated. 1N HCl/MeOH (400 μl) was addedand the mixture was shaken for 30 min. The mixture was evaporated thendried in vacuo to give the product.

LCMS Ex. Structure (condition A) 8C

t_(R) = 3.07 min m/e = 545 (M + H)⁺ 8D

t_(R) = 3.52 min m/e = 621 (M + H)⁺ 8E

t_(R) = 3.92 min m/e = 621 (M + H)⁺ 8F

t_(R) = 4.15 min m/e = 627 (M + H)⁺ 8G

t_(R) = 4.12 min m/e = 627 (M + H)⁺ 8H

t_(R) = 4.13 min m/e = 629 (M + H)⁺ 8I

t_(R) = 4.18 min m/e = 629 (M + H)⁺ 8J

t_(R) = 4.15 min m/e = 631 (M + H)⁺ 8K

t_(R) = 4.37 min m/e = 635 (M + H)⁺ 8L

t_(R) = 3.92 min m/e = 637 (M + H)⁺ 8M

t_(R) = 3.89 min m/e = 639 (M + H)⁺ 8N

t_(R) = 3.88 min m/e = 643 (M + H)⁺ 8O

t_(R) = 4.04 min m/e = 647 (M + H)⁺ 8P

t_(R) = 4.18 min m/e = 647 (M + H)⁺ 8Q

t_(R) = 4.23 min m/e = 647 (M + H)⁺ 8R

t_(R) = 4.18 min m/e = 647 (M + H)⁺ 8S

t_(R) = 4.15 min m/e = 647 (M + H)⁺ 8T

t_(R) = 4.02 min m/e = 647 (M + H)⁺ 8U

t_(R) = 3.63 min m/e = 531 (M + H)⁺ 8V

t_(R) = 3.86 min m/e = 585 (M + H)⁺ 8W

t_(R) = 3.92 min m/e = 593 (M + H)⁺ 8X

t_(R) = 3.97 min m/e = 593 (M + H)⁺ 8Y

t_(R) = 4.03 min m/e = 593 (M + H)⁺ 8Z

t_(R) = 4.01 min m/e = 593 (M + H)⁺ 8AA

t_(R) = 3.87 min m/e = 597 (M + H)⁺ 8BB

t_(R) = 3.95 min m/e = 597 (M + H)⁺ 8CC

t_(R) = 3.97 min m/e = 597 (M + H)⁺ 8DD

t_(R) = 4.11 min m/e = 605 (M + H)⁺ 8EE

t_(R) = 4.15 min m/e = 607 (M + H)⁺ 8FF

t_(R) = 3.99 min m/e = 609 (M + H)⁺ 8GG

t_(R) = 3.96 min m/e = 609 (M + H)⁺ 8HH

t_(R) = 3.94 min m/e = 613 (M + H)⁺ 8II

t_(R) = 4.07 min m/e = 613 (M + H)⁺ 8JJ

t_(R) = 4.11 min m/e = 613 (M + H)⁺ 8KK

t_(R) = 4.05 min m/e = 615 (M + H)⁺ 8LL

t_(R) = 4.07 min m/e = 619 (M + H)⁺ 8MM

t_(R) = 4.49 min m/e = 649 (M + H)⁺ 8NN

t_(R) = 4.20 min m/e = 653 (M + H)⁺ 8OO

t_(R) = 4.36 min m/e = 655 (M + H)⁺ 8PP

t_(R) = 3.98 min m/e = 657 (M + H)⁺ 8QQ

t_(R) = 4.13 min m/e = 657 (M + H)⁺ 8RR

t_(R) = 4.41 min m/e = 671 (M + H)⁺ 8SS

t_(R) = 3.88 min m/e = 598 (M + H)⁺ 8TT

t_(R) = 3.87 min m/e = 604 (M + H)⁺ 8UU

t_(R) = 3.93 min m/e = 604 (M + H)⁺ 8VV

t_(R) = 3.97 min m/e = 604 (M + H)⁺ 8WW

t_(R) = 3.83 min m/e = 657 (M + H)⁺ 8XX

t_(R) = 3.83 min m/e = 657 (M + H)⁺ 8YY

t_(R) = 3.82 min m/e = 631 (M + H)⁺ 8ZZ

t_(R) = 4.18 min m/e = 730 (M + H)⁺ 8AAA

t_(R) = 3.91 min m/e = 559 (M + H)⁺ 8BBB

t_(R) = 3.57 min m/e = 583 (M + H)⁺ 8CCC

t_(R) = 3.80 min m/e = 614 (M + H)⁺ 8DDD

t_(R) = 3.92 min m/e = 621 (M + H)⁺ 8EEE

t_(R) = 3.72 min m/e = 636 (M + H)⁺ 8FFF

t_(R) = 4.02 min m/e = 652 (M + H)⁺ 8GGG

t_(R) = 4.09 min m/e = 662 (M + H)⁺ 8HHH

t_(R) = 3.76 min m/e = 657 (M + H)⁺ 8III

t_(R) = 4.44 min m/e = 683 (M + H)⁺

Example 9

Step 1:

A mixture of the product of Example 8A, Step 2 (419 mg, 1.13 mmol) andbenzophenone imine (240 mg, 1.28 mmol) in CH₂Cl₂ (20 ml) was refluxedfor 16 h. The mixture was concentrated and purified by columnchromatography (gradient MeOH/CH₂Cl₂ 0-6%) to give the product (376 mg,62%). MS m/e 536 (M+H)⁺.

Step 2:

A mixture of the product of Step 1 (133 mg, 0.248 mmol), Et₃N (35 PI,0.25 mmol), and acetic anhydride (25 mg, 0.25 mmol) in CH₂Cl₂ (10 ml)was stirred in an ice-water bath for 30 min then at RT for 16 h. Themixture was diluted with CH₂Cl₂ (40 ml) and washed with 1N NaOH (20 ml).The organic layer was dried (MgSO₄), concentrated, and purified by PTLC(3% MeOH/CH₂Cl₂) to give the product (116 mg, 81%). MS m/e 578 (M+H)⁺.

Step 3:

A solution of the product of Step 2 (116 mg, 0.200 mmol) andhydroxylamine hydrochloride (186 mg, 2.67 mmol) in EtOH (8 ml) and water(2 ml) was heated to 5° C. for 2 h. The mixture was concentrated and theresidue was partitioned between CH₂Cl₂ (50 ml) and 1N NaOH (20 ml). Theorganic layer was dried (MgSO₄), concentrated, and purified by PTLC (8%MeOH/CH₂Cl₂) to give the product (89 mg, 100%). MS m/e 414 (M+H)⁺.

Step 4:

A mixture of the product of Step 3 (89 mg, 0.22 mmol) and Preparation2LL (39 mg, 0.21 mmol) were coupled in analogy to the procedure ofExample 5A Step 5. The crude product was purified by PTLC (5%MeOH/CH₂Cl₂) to give the product (49 mg, 39%). MS m/e 581 (M+H)⁺.

Step 5:

A mixture of the product of Step 4 (49 mg, 0.084 mmol) and TFA (0.9 ml)in CH₂Cl₂ (4 ml) was stirred in an ice-water bath for 30 min then at RTfor 3 h. The mixture was diluted with CH₂Cl₂ (40 ml) and washed withaqueous NH₄OH (15 ml). The organic layer was dried (MgSO₄),concentrated, and purified by PTLC (8% MeOH/CH₂Cl₂) to give the product(30 mg, 73%). ¹H NMR (CDCl₃) δ 7.21 (d, 1H, J=8.8 Hz), 6.75 (m, 2H),6.62 (m, 1H), 4.0-4.4 (m, 3H), 2.9-3.7 (m, 11H), 2.71 (m, 3H), 2.45 (m,1H), 2.28 (m, 1H), 2.09 (s, 3H), 1.44 (m, 2H), 1.26 (m, 2H), 0.88 (m,3H). LCMS (Conditions A): t_(R)=2.17 min; m/e 481 (M+H)⁺.

By essentially the same procedure set forth in Example 9A, the followingexamples were prepared.

LCMS EX. Structure (Conditions A) 9B

t_(R) = 2.86 min m/e 543 (M + H)⁺ 9C

t_(R) = 2.60 min m/e 510 (M + H)⁺ 9D

t_(R) = 2.98 min m/e 573 (M + H)⁺

Example 10A

Step 1:

To a solution of the product of Example 5A, Step 4 (326 mg, 0.687 mmol)in THF (3 ml) was added 2M BH₃—SMe₂ in THF (2.0 ml) and the mixture washeated to 60° C. for 16 h. The mixture was treated with saturated citricacid (40 ml) and extracted with EtOAc (3×30 ml). The combined organiclayer was evaporated to dryness and the residue was partitioned betweenCH₂Cl₂ (60 ml) and aqueous NH₄OH (20 ml). The organic layer was dried(MgSO₄) and concentrated to give the product (190 mg, 60%). MS m/e 462(M+H)⁺.

Step 2:

A mixture of the product of Step 1 (527 mg, 2.80 mmol) and Preparation2LL were couple in analogy to the procedure of Example 5A Step 5 to givethe product (832 mg, 70%) as a yellow oil.

Step 3:

A suspension of the product of Step 2 (832 mg, 1.32 mmol) and Pd(OH)₂/C(670 mg) in MeOH (15 ml) was stirred under a H₂ atmosphere for 6 h. Thereaction mixture was filtered and evaporated to give the product (617mg, 87%). MS m/e 539 (M+H)⁺.

Step 4:

A mixture of the product of Step 3 (18 mg, 0.034 mmol), K₂CO₃ (25 mg,0.18 mmol) and 3-picolyl chloride hydrochloride (13 mg, 0.08 mmol) inDMF (1 ml) was stirred at RT for 18 h. The reaction mixture wasfiltered, concentrated and the residue was subjected to preparative HPLC(Conditions B) to give the alkylated product. The product was stirredwith 1:4 TFA/CH₂Cl₂ (2 ml) for 2 h, then concentrated. The residue wasdissolved in 1N HCl/MeOH and evaporated to give the hydrochloride saltof the product (9 mg) as a light yellow solid. LCMS (Conditions A)t_(R)=2.13 min, m/e 530 (M+H)⁺.

Using the appropriate alkylating reagent and essentially the sameprocedure described for Example 10A, the following Examples wereprepared.

LCMS Ex. Reagent Structure (Conditions A) 10B

t_(R) = 2.15 min; 496 (M + H)⁺ 10C

t_(R) = 2.28 min; 524 (M + H)⁺ 10D

t_(R) = 2.38 min; 552 (M + H)⁺ 10E

t_(R) = 2.28 min; 550 (M + H)⁺ 10F

t_(R) = 2.41 min; 564 (M + H)⁺ 10G

t_(R) = 2.17 min; 566 (M + H)⁺ 10H

t_(R) = 2.42 min; 536 (M + H)⁺ 10I

t_(R) = 2.22 min; 530 (M + H)⁺ 10J

t_(R) = 2.53 min; 548 (M + H)⁺ 10K

t_(R) = 2.61 min; 534 (M + H)⁺ 10L

t_(R) = 2.51 min; 550 (M + H)⁺ 10M

t_(R) = 2.17 min; 533 (M + H)⁺

Example 11A

The product was prepared according to the procedure of Example 2A,except that N-Boc-cis-4-benzyloxy-D-proline was used in place ofN-Boc-D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, andPreparation 2A was used in place of Preparation 3A. The product wasobtained as a mixture of two diastereomers that were separated byreverse-phase preparative HPLC (Conditions C). Diastereomer 1: ¹H NMR(400 MHz, CD₃OD) δ 8.40 (bs, 1H), 7.20-7.35 (m, 5H), 6.73-6.85 (m, 3H),4.51 (m, 2H), 4.29 (m, 1H), 3.99 (m, 1H), 3.81 (m, 1H), 3.68 (m, 1H),3.35-3.46 (m, 3H), 3.17 (m, 3H), 2.94-3.15 (m, 1H), 2.34-2.64 (m, 4H),2.13 (m, 1H), 1.97 (m, 1H), 1.43 (m, 2H), 1.25 (m, 2H), 0.88 (m, 3H);LCMS (Conditions A) t_(R)=4.28 min, 530 (M+H)⁺. Diastereomer 2: ¹H NMR(400 MHz, CD₃OD). δ 8.45 (bs, 1H), 7.20-7.40 (m, 5H), 6.74-6.95 (m, 3H),4.55 (m, 2H), 4.28 (m, 1H), 4.22 (m, 1H), 4.01 (m, 1H), 3.76 (m, 1H),3.62 (m, 1H), 3.37 (m, 2H), 3.17-3.30 (m, 2H), 3.09 (m, 1H), 2.98 (m,1H), 2.78 (m, 1H), 2.30-2.60 (m, 4H), 2.11 (m, 1H), 1.36 (m, 2H), 1.18(m, 2H), 0.88 (m, 3H); LCMS (conditions A) t_(R)=4.38 min, 530 (M+H)⁺.

Using the appropriate carboxylic acid the following Examples wereprepared.

LCMS Ex. Preparation Structure (Conditions A) 11B

t_(R) = 3.58 min; 474 (M + H)⁺ 11C

t_(R) = 3.64 min; 474 (M + H)⁺ 11D

t_(R) = 3.85 min; 502 (M + H)⁺ 11E

t_(R) = 3.98 min; 516 (M + H)⁺ 11F

t_(R) = 4.00 min; 516 (M + H)⁺ 11G

t_(R) = 3.67 min; 544 (M + H)⁺ 11H

t_(R) = 3.74 min; 558 (M + H)⁺ 11I

t_(R) = 2.91 min; 560 (M + H)⁺ 11J

t_(R) = 2.66 min; 559 (M + H)⁺ 11K

t_(R) = 3.21 min; 528 (M + H)⁺ 3.29 min; 528 (M + H)⁺ 11L

t_(R) = 3.06 min; 560 (M + H)⁺ 11M

t_(R) = 2.71 min; 546 (M + H)⁺ 11N

t_(R) = 3.30 min; 546 (M + H)⁺ 3.38 min; 546 (M + H)⁺ 11O

t_(R) = 3.31 min; 560 (M + H)⁺ 11P

t_(R) = 3.32 min; 560 (M + H)⁺ 11Q

t_(R) = 3.97 min; 572 (M + H)⁺ 11R

t_(R) = 3.24 min; 544 (M + H)⁺ 11S

t_(R) = 4.28 min; 544 (M + H)⁺ 11T

t_(R) = 4.25 min; 564 (M + H)⁺ 11U

t_(R) = 3.55 min; 582 (M + H)⁺ 11V

t_(R) = 3.39 min; 599 (M + H)⁺ 11W

t_(R) = 3.54 min; 632 (M + H)⁺ 11X

t_(R) = 3.26 min; 582 (M + H)⁺ 11Y

t_(R) = 3.60 min; 578 (M + H)⁺ t_(R) = 3.67 min; 578 (M + H)⁺ 11Z

t_(R) = 3.20 min; 582 (M + H)⁺ t_(R) = 3.25 min; 582 (M + H)⁺ 11AA

t_(R) = 2.64 min; 565 (M + H)⁺ t_(R) = 2.65 min; 565 (M + H)⁺ 11BB

t_(R) = 2.51 min; 565 (M + H)⁺ 11CC

t_(R) = 3.36 min; 554 (M + H)⁺ 3.41 min; 554 (M + H)⁺ 11DD

t_(R) = 3.47 min; 570 (M + H)⁺ 11EE

t_(R) = 3.46 min; 570 (M + H)⁺ 11FF

t_(R) = 3.05 min; 571 (M + H)⁺ 11GG

t_(R) = 3.40 min; 638 (M + H)⁺ 3.45 min; 638 (M + H)⁺ 11HH

t_(R) = 3.82 min; 613 (M + H)⁺ 3.89 min; 613 (M + H)⁺ 11II

t_(R) = 3.61 min; 558 (M + H)⁺ 11JJ

t_(R) = 3.72 min; 572 (M + H)⁺ 11KK

t_(R) = 4.54 min; 586 (M + H)⁺ 11LL

t_(R) = 4.64 min; 621 (M + H)⁺ 11MM

t_(R) = 3.38 min; 584 (M + H)⁺ 11NN

t_(R) = 3.65 min; 612 (M + H)⁺ 11OO

t_(R) = 3.63 min; 600 (M + H)⁺ 11PP

t_(R) = 4.02 min; 634 (M + H)⁺ 11QQ

t_(R) = 3.65 min; 559 (M + H)⁺ 11RR

t_(R) = 3.46 min; 573 (M + H)⁺ 11SS

t_(R) = 3.88 min; 587 (M + H)⁺ 11TT

t_(R) = 4.50 min; 635 (M + H)⁺ 11UU

t_(R) = 3.33 min; 565 (M + H)⁺ 11VV

t_(R) = 4.32 min; 621 (M + H)⁺ 11WW

t_(R) = 3.46 min; 573 (M + H)⁺

Example 12A

Step 1:

Cis-4-hydroxy-D-proline was converted into(4R)-(1-tert-butoxycarbonyl)-4-hydroxy-D-proline benzyl ester based onthe procedure reported for the synthesis of(4S)-1-tert-butoxycarbonyl)-4-hydroxy-L-proline benzyl ester fromcis-4-hydroxy-L-proline (Webb et al. J. Org. Chem. (1991), 56,3009-3016). Mitsunobu inversion to give(4S)-1-(tert-butoxycarbonyl)-4-hydroxy-D-proline benzyl ester wasadapted from the reported procedure (Lowe et al. J. Chem. Soc. PerkinTrans. 1 (1997), 539-546) for the synthesis of(4S)-1-tert-butoxycarbonyl)-4-hydroxy-D-proline methyl ester from(4R)-1-(tert-butoxycarbonyl)-4-hydroxy-D-proline methyl ester.

Step 2:

(4S)-1-(tert-butoxycarbonyl)-4-hydroxy-D-proline benzyl ester wasconverted into (4R)-1-(tert-butoxycarbonyl)-4-phenoxy-D-proline benzylester based on the reported protocol (Bellier et al. J. Med. Chem.(1997), 40, 3947-3956) for the corresponding methyl ester.

Step 3:

The product of Step 2 was converted to Example 12A in analogy to theprocedure of Example 2A, except that Preparation 2A was used in place ofPreparation 3A. LCMS (conditions A): t_(R) (isomer 1)=3.23 min, m/e 516(M+H)⁺; t_(R) (isomer 2)=3.36 min, m/e 516 (M+H)⁺.

Using the appropriate carboxylic acid, the following Examples wereprepared.

LCMS Example Preparation Structure (Conditions A) 12B

t_(R) = 3.32 min; 570 (M + H)⁺ 12C

t_(R) = 3.60 min; 598 (M + H)⁺ 12D

t_(R) = 3.94 min; 586 (M + H)⁺ 12E

t_(R) = 3.69 min; 620 (M + H)⁺ 12F

t_(R) = 3.74 min; 586 (M + H)⁺ 12G

t_(R) = 3.92 min; 584 (M + H)⁺ 3.99 min; 584 (M + H)⁺ 12H

t_(R) = 3.21 min; 546 (M + H)⁺ 12I

t_(R) = 3.44 min; 559 (M + H)⁺

Example 13A

Step 1:

(4R)-1-tert-butoxycarbonyl-4-benzyloxy-D-proline benzyl ester (Bellieret al. J. Med. Chem. (1997), 40, 3947-3956) was converted into theproduct in analogy to the procedure of Example 2A, Steps 1 through 5,except that (4R)-1-tert-butoxycarbonyl-4-benzyloxy-D-proline benzylester was used in place of methylN-Boc-D-1,2,3,4-tetrahydroquinoline-3-carboxylate. LCMS (Conditions A)t_(R)=4.84 min: m/e 925 (2M+H)—, 463 (M+H)⁺, 407 (M-tBu+H), 363(M-Boc+H)⁺.

Step 2:

Preparation 7 (40 mg) and Et₃N (0.05 ml) was added to a stirred solutionof the product of Step 1 (10 mg) in CH₂Cl₂ (1 ml). After 24 h, thereaction mixture was concentrated and the residue was subjected to HPLC(Conditions B) to give the coupled product. Deprotection of the coupledproduct in analogy to the procedure of Example 5A, Step 6 gave theproduct. LCMS (Conditions A) t_(R)=3.21 min; 531 (M+H)⁺.

In analogy to Example 13A, using the appropriate Preparations andintermediates, the following Examples were prepared:

LCMS Ex. Preparation Structure (Conditions A) 13B

t_(R) = 3.87 min; 601 (M + H)⁺ 13C

t_(R) = 3.60 min; 518 (M + H)⁺ 13D

t_(R) = 3.17 min; 517 (M + H)⁺ 13E

t_(R) = 3.81 min; 587 (M + H)⁺ 13F

t_(R) = 3.55 min; 504 (M + H)⁺ 13G

t_(R) = 3.68 min; 531 (M + H)⁺

Example 14A

Step 1:

A mixture of (N-benzyloxycarbonyl)azetidine-3-carboxylic preparedaccording to Macdonald et al., J. Med. Chem., (2002); 45, 3878 (325 mg,1.38 mmol), and the product of Example 13A, Step 1 (320 mg, 0.69 mmol),HOAt (330 mg, 2.42 mmol), HATU (790 mg, 2.08 mmol), and Et₃N (580 μl,4.15 mmol) in DMF (8 ml) was stirred at RT for 16 h. The mixture waspartitioned between EtOAc and water, and the organic layer was washedwith water and sat'd NaCl, dried (MgSO₄), concentrated, and purified bychromatography (SiO₂, 0-2% MeOH/CH₂Cl₂) to give the coupled product (402mg, 86%): LCMS (Conditions A) t_(R)=4.99 min, m/e 680 (M+H). The coupledproduct (220 mg, 0.323 mmol) and 20% Pd(OH)₂/C (20 mg) in EtOH (11 ml)was stirred under 50 psi H₂, and the mixture was filtered aftercompletion of the reaction as monitored by TLC. The resulting residuewas subjected to PTLC (8% (2M NH₃/MeOH)/CH₂Cl₂) to give the product.LCMS (Conditions A): t_(R)=4.49 min: m/e 546 (M+H), 490 (M-^(t)Bu+H),446 (M-Boc+H).

Step 2:

The product of Step 1 was coupled with pentanoic acid by essentially theprocedure of Example 5A, Step 5. The coupled product was subjected toTFA in analogy to Example 5A, Step 6, to give the product. LCMS(conditions A) t_(R)=4.90 min: MS m/e 580 (M+H), 562 (M−H₂O+H).

Using the appropriate carboxylic acid, the following Examples wereprepared from the product of Example 14, Step 1.

LCMS Ex. Carboxylic Acid Structure (Conditions A) 14B

t_(R) = 4.59 min; 572 (M + H)⁺ 14C

t_(R) = 4.33 min; 556 (M + H)⁺ 14D

t_(R) = 4.08 min; 514 (M + H)⁺ 14E

t_(R) = 3.42 min; 559 (M + H)⁺

The following Examples were prepared by reaction of the product ofExample 14, Step 1, with the appropriate sulfonyl chloride (1.2 equiv)and Et₃N (2.0 equiv) in CH₂Cl₂ at RT. Upon completion of the reaction,the reaction mixture was diluted with CH₂Cl₂/water, washed with brine(1×), and the organic layer dried (MgSO₄), and concentrated. Treatmentof the residue with TFA in analogy to the procedure of Example 5A, Step6, gave the products.

LCMS Ex. Sulfonyl Chloride Structure (Conditions A) 14F

t_(R) = 4.34 min; 567 (M + H)⁺ 14G

t_(R) = 4.17 min; 552 (M + H)⁺ 14H MeSO₂Cl

t_(R) = 3.86 min; 524 (M + H)⁺

Example 15A

Step 1:

To a RT solution of 3-benzyl-4-imidazolidinone (1.07 g, 6.07 mmol),prepared according to Pinza, et al. Liebigs Ann. Chem. (1988), 993, inCH₂Cl₂ (80 ml) was added Et₃N (7 drops) and Boc₂O (1.39 g, 6.38 mmol).After 20 h, the reaction mixture was diluted with water and stirredvigorously for 10 min. The phases were separated, and the aqueous phasewas extracted with CH₂Cl₂ (2×). The organic portions were combined,washed with brine, dried over MgSO₄, filtered and concentrated. Thecrude residue was purified by chromatography (silica, 0→50%EtOAc/hexanes) to give the desired product (1.37 g, 82%).

Step 2:

To a −78° C. solution of diisopropylamine (0.17 ml, 1.20 mmol) in THF (1ml) was added n-BuLi (1.55 M in hexanes, 0.74 ml, 1.15 mmol). After 5min, the mixture was warmed to 0° C., and after an additional 20 min, itwas cooled back to −78° C. To this mixture was added a −78° C. solutionof the product of Step 1 (304 mg, 1.10 mmol) in THF (3.5 ml). Theresulting mixture was stirred at −78° C. for 1 h. At that time, a −78°C. solution of the product of Preparation 14 (366 mg, 1.00 mmol) in THF(2 ml) was added. The resulting mixture was stirred for 1.5 h at −78° C.and then was diluted with water and Et₂O. After warming to RT, thephases were separated, and the aqueous phase was extracted with Et₂O(3×). The organic portions were combined, washed with brine, dried overMgSO₄, filtered and concentrated. The crude residue was purified bychromatography (silica, 0→65% EtOAc/hexanes) to give the desired product(288 mg, 45%).

Step 3:

A flask was charged with the product of Step 2 (325 mg, 0.506 mmol),EtOAc (10 ml), AcOH (0.050 ml) and Pd(OH)₂/C (200 mg). The flask wasevacuated and re-filled with H₂ from a balloon (7×) and then kept underH₂ balloon pressure. After 20 h, additional Pd(OH)₂/C (100 mg) was addedfollowed by AcOH (0.050 ml). After an additional 6 h, the mixture wasfiltered through Celite with copious EtOAc washes, and the resultingfiltrate was concentrated. The crude residue was purified bychromatography (silica, 0→15% 7N NH₃/MeOH in CH₂Cl₂) followed by PTLC(5% 7N NH₃/MeOH in CH₂Cl₂) to give the desired product (87 mg, 37%). ¹HNMR (400 MHz, CDCl₃) δ 7.28 (m, 5H), 6.76-6.63 (m, 3H), 4.72-4.38 (m,5H), 3.95 (d, J=8.8 Hz, 1H), 3.32 (br d, J=13.2 Hz, 1H), 3.09 (m, 0.2H),2.77 (m, 1H), 2.67 (m, 0.2H), 2.44 (dd, J=15.2, 10.0 Hz), 1.45 (s, 9H).

Step 4:

To a solution of Preparation 2A (13 mg, 0.072 mmol) and the product ofStep 3 (30 mg, 0.065 mmol) in of DMF (1 ml) was added PyBOP (44 mg,0.085 mmol) and DIEA (0.045 ml, 0.26 mmol). The mixture was stirred atRT for one day. It was diluted with EtOAc (1 ml) and hexane (1 ml). Themixture was washed with water (3×1 ml), the organic layer was dried(Na₂SO₄) and concentrated in vacuo. The residue was purified bychromatography (SiO₂, 70% EtOAc/hexane) to give coupled product (24 mg,60%). This coupled product was treated with 4N HCl in dioxane (2 ml) for30 min. The mixture was concentrated in vacuo to give product (26.3 mg,100%). ¹H NMR (400 MHz, CD₃OD) δ 8.20 (m, 1H), 7.31 (m, 5H), 6.84 (m,2H), 6.78 (m, 1H), 4.72-4.40 (m, 5H), 4.34 (m, 1H), 4.22 (m, 1H), 3.40(m, 2H), 3.30-2.90 (m, 5H), 2.78 (m, 1H), 2.42 (m, 1H), 2.22 (m, 1H),1.42 (m, 2H), 1.23 (m, 2H), 0.88 (t, J=7.6 Hz, 3H); LCMS t_(R)=3.18 min,529 (M+H).

By essentially the same procedure set forth for Example 15A, and usingthe appropriate Preparations, the following compounds were prepared:

LCMS Ex. Preparation Structure (Conditions A) 15B

t_(R) = 3.35 min, 557 (M + H) 15C

t_(R) = 3.38 min, 543 (M + H) 15D

t_(R) = 2.97 min, 515 (M + H)

BACE-1 Cloning, Protein Expression and Purification

A predicted soluble form of human BACE1 (sBACE1, corresponding to aminoacids 1-454) was generated from the full length BACE1 cDNA (full lengthhuman BACE1 cDNA in pcDNA4/mycHisA construct; University of Toronto) byPCR using the advantage-GC cDNA PCR kit (Clontech, Palo Alto, Calif.). AHindIII/PmeI fragment from pcDNA4-sBACE1myc/His was blunt ended usingKlenow and subcloned into the Stu I site of pFASTBACI(A) (Invitrogen). AsBACE1mycHis recombinant bacmid was generated by transposition inDH10Bac cells(GIBCO/BRL). Subsequently, the sBACE1mycHis bacmidconstruct was transfected into sf9 cells using CellFectin (Invitrogen,San Diego, Calif.) in order to generate recombinant baculovirus. Sf9cells were grown in SF 900-II medium (Invitrogen) supplemented with 3%heat inactivated FBS and 0.5× penicillin/streptomycin solution(Invitrogen). Five milliliters of high titer plaque purifiedsBACEmyc/His virus was used to infect 1 L of logarithmically growing sf9cells for 72 hours. Intact cells were pelleted by centrifugation at3000×g for 15 minutes. The supernatant, containing secreted sBACE1, wascollected and diluted 50% v/v with 100 mM HEPES, pH 8.0. The dilutedmedium was loaded onto a Q-sepharose column. The O-sepharose column waswashed with Buffer A (20 mM HEPES, pH 8.0, 50 mM NaCl).

Proteins, were eluted from the Q-sepharose column with Buffer B (20 mMHEPES, pH 8.0, 500 mM NaCl). The protein peaks from the Q-sepharosecolumn were pooled and loaded onto a Ni-NTA agarose column. The Ni-NTAcolumn was then washed with Buffer C (20 mM HEPES, pH 8.0, 500 mM NaCl).Bound proteins were then eluted with Buffer D (Buffer C+250 mMimidazole). Peak protein fractions as determined by the Bradford Assay(Biorad, CA) were concentrated using a Centricon 30 concentrator(Millipore). sBACE1 purity was estimated to be 90% as assessed bySDS-PAGE and Commassie Blue staining. N-terminal sequencing indicatedthat greater than 90% of the purified sBACE1 contained the prodomain;hence this protein is referred to as sproBACE1.

Peptide Hydrolysis Assay

The inhibitor, 25 nM EuK-biotin labeled APPsw substrate(EuK-KTEEISEVNLDAEFRHDKC-biotin; CIS-Bio International, France), 5 μMunlabeled APPsw peptide (KTEEISEVNLDAEFRHDK; American Peptide Company,Sunnyvale, Calif.), 7 nM sproBACE1, 20 mM PIPES pH 5.0, 0.1% Brij-35(protein grade, Calbiochem, San Diego, Calif.), and 10% glycerol werepreincubated for 30 min at 30° C. Reactions were initiated by additionof substrate in a 5 μl aliquot resulting in a total volume of 25 μl.After 3 hr at 30° C. reactions were terminated by addition of an equalvolume of 2× stop buffer containing 50 mM Tris-HCl pH 8.0, 0.5 M KF,0.001% Brij-35, 20 g/ml SA-XL665 (cross-linked allophycocyanin proteincoupled to streptavidin; CIS-Bio International, France) (0.5 μg/well).Plates were shaken briefly and spun at 1200×g for 10 seconds to pelletall liquid to the bottom of the plate before the incubation. HTRFmeasurements were made on a Packard Discovery® HTRF plate reader using337 nm laser light to excite the sample followed by a 50 μs delay andsimultaneous measurements of both 620 nm and 665 nm emissions for 400μs.

IC₅₀ determinations for inhibitors, (I), were determined by measuringthe percent change of the relative fluorescence at 665 nm divided by therelative fluorescence at 620 nm, (665/620 ratio), in the presence ofvarying concentrations of I and a fixed concentration of enzyme andsubstrate. Nonlinear regression analysis of this data was performedusing GraphPad Prism 3.0 software selecting four parameter logisticequation, that allows for a variable slope.Y=Bottom+(Top−Bottom)/(1+10̂((LogEC50-X)*Hill Slope)); X is the logarithmof concentration of 1, Y is the percent change in ratio and Y starts atbottom and goes to top with a sigmoid shape.

Compounds of the present invention have an IC₅₀ range from about 0.1 toabout 26,000 nM, preferably about 0.1 to about 1000 nM, more preferablyabout 0.1 to about 100 nM. Compounds of the preferred stereochemistryhave IC₅₀ values in a range of about 0.1 to about 500 nM, preferablyabout 0.1 to about 100 nM. Example 5FF has as IC₅₀ of 1 nM.

In the aspect of the invention relating to a combination of a compoundof formula I with a cholinesterase inhibitor, acetyl- and/orbutyrylchlolinesterase inhibitors can be used. Examples ofcholinesterase inhibitors are tacrine, donepezil, rivastigmine,galantamine, pyridostigmine and neostigmine, with tacrine, donepezil,rivastigmine and galantamine being preferred.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two tofour divided doses.

When a compound of formula I is used in combination with a β-secretaseinhibitors other than those of formula I, an HMG-CoA reductaseinhibitor, a gamma-secretase inhibitor, a non-steroidalanti-inflammatory agent, an N-methyl-D-aspartate receptor antagonist, acholinesterase inhibitor or an anti-amyloid antibody to treat acognitive disorder or neurodegenerative disorder, the active componentsmay be co-administered simultaneously or sequentially, or a singlepharmaceutical composition comprising a compound of formula I and one ofthe other agents in a pharmaceutically acceptable carrier can beadministered. The components of the combination can be administeredindividually or together in any conventional oral or parenteral dosageform such as capsule, tablet, powder, cachet, suspension, solution,suppository, nasal spray, etc. The dosage of the β-secretase inhibitorsother than those of formula I, HMG-CoA reductase inhibitor,gamma-secretase inhibitor, non-steroidal anti-inflammatory agent,N-methyl-D-aspartate receptor antagonist, cholinesterase inhibitor oranti-amyloid antibody can be determined from published material, and mayrange from 0.001 to 100 mg/kg body weight.

When separate pharmaceutical compositions of a compound of formula I anda β-secretase inhibitors other than those of formula I, an HMG-CoAreductase inhibitor, a gamma-secretase inhibitor, a non-steroidalanti-inflammatory agent, an N-methyl-D-aspartate receptor antagonist, acholinesterase inhibitor or an anti-amyloid antibody are to beadministered, they can be provided in a kit comprising in a singlepackage, one container comprising a compound of formula I in apharmaceutically acceptable carrier, and a separate container comprisingthe other agent in a pharmaceutically acceptable carrier, with thecompound of formula I and the other agent being present in amounts suchthat the combination is therapeutically effective. A kit is advantageousfor administering a combination when, for example, the components mustbe administered at different time intervals or when they are indifferent dosage forms.

The invention also includes multi-agent compositions, kits and methodsof treatment, e.g., a compound of formula I can be administered incombination with an HMG-CoA reductase inhibitor and a non-steroidalanti-inflammatory agent.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1-33. (canceled)
 34. A method of treating a cognitive orneurodegenerative disease comprising administering to a patient in needof such treatment an effective amount of a compound, or apharmaceutically acceptable salt thereof, said compound having astructure according to Formula (I):

wherein: R¹ is

X is —O—, —C(R¹⁴)₂— or —N(R)—; Z is —C(R¹⁴)₂— or —N(R)—; t is 0, 1, 2 or3; each R is independently selected from the group consisting of H,alkyl, alkoxy, alkoxyalkyl, phenylalkyl, alkenyl, pyridylmethyl,furanylmethyl, thienylmethyl, thiazolylmethyl, cycloalkyl, andcycloalkylalkyl, wherein said alkyl, said alkoxy, said alkoxyalkyl, saidphenylalkyl, said alkenyl, said pyridylmethyl, said furanylmethyl, saidthienylmethyl, said thiazolylmethyl, said cycloalkyl, and saidcycloalkylalkyl are unsubstituted or substituted by from 1 to 5independently selected R³² groups; R² is H, alkyl, phenyl, orphenylalkyl, wherein said phenyl and said phenylalkyl are unsubstitutedor substituted by from 1 to 5 independently selected R³² groups; R³ is Hor alkyl; R⁴ is H or alkyl; R⁵ is H or alkyl; each R¹⁴ is independentlyselected from the group consisting of H, alkyl, alkenyl, halo, —CN,haloalkyl, phenyl, phenylalkyl, cycloalkyl, R⁴¹ is alkyl, cycloalkyl,—SO₂(alkyl), —C(O)alkyl, —C(O)-cycloalkyl or -alkyl-NH—C(O)CH₃; R⁶ andR⁷ are independently selected from the group consisting of H and alkyl,or R⁶ and R⁷, together with the ring carbon to which they are attached,form —C(O)—; R⁸ and R⁹ are independently selected from the groupconsisting of H and alkyl, or R⁸ and R⁹, together with the ring carbonto which they are attached, form —C(O)—; R¹² and R¹³ are independentlyselected from the group consisting of H and alkyl, wherein said alkyl isunsubstituted or substituted by from 1 to 5 independently selected R³²groups, or R¹² and R¹³, together with the ring carbon to which they areattached, form —C(O)—; R¹⁸ is H, alkyl, phenyl, phenylalkyl, pyridyl,oxazolyl, pyrazinyl, thienyl, imidazolyl, pyridylalkyl, oxazolylalkyl,pyrazinylalkyl, thienylalkyl, or imidazolylalkyl, wherein said alkyl,said phenyl, said phenylalkyl, said pyridyl, said oxazolyl, saidpyrazinyl, said thienyl, said imidazolyl, said pyridylalkyl, saidoxazolylalkyl, said pyrazinylalkyl, said thienylalkyl, and saidimidazolylalkyl, are each unsubstituted or substituted by from 1 to 4independently selected R³² groups; R¹⁹ is H, alkyl, phenyl, phenylalkyl,pyridyl, oxazolyl, pyrazinyl, thienyl, imidazolyl, pyridylalkyl,oxazolylalkyl, pyrazinylalkyl, thienylalkyl, or imidazolylalkyl, —SOR⁸,—SO₂R¹⁸ or —CN, wherein said alkyl, said phenyl, said phenylalkyl, saidpyridyl, said oxazolyl, said pyrazinyl, said thienyl, said imidazolyl,said pyridylalkyl, said oxazolylalkyl, said pyrazinylalkyl, saidthienylalkyl, and said imidazolylalkyl, are each unsubstituted orsubstituted by from 1 to 4 independently selected R³² groups; and eachR³² group is independently selected from the group consisting of halo,alkyl, alkoxy, —OH, phenyl, phenoxy, phenylalkyl, —NO₂, —CN, haloalkyl,and haloalkoxy, or two R³² groups on the same ring carbon atom are takentogether to form ═O.
 35. The method of claim 34, wherein R³, R⁴ and R⁵are hydrogen and R² is phenylalkyl, said phenylalkyl being unsubstitutedor substituted by from 1 to 5 independently selected R³² groups.
 36. Themethod of claim 35, wherein R² is benzyl, wherein said benzyl isunsubstituted or substituted by from 1 to 5 independently selected R³²groups.
 37. The method of claim 34, wherein R¹ is


38. The method of claim 34, wherein R¹ is

t is 1 and X is —C(R¹⁴)₂— or —N(R)—.
 39. The method of claim 38, whereinX is —C(R¹⁴)₂—, R¹⁴ is hydrogen, alkyl, alkenyl, cycloalkyl or benzyl,and R is alkyl, alkoxy, alkoxyalkyl, unsubstituted phenylalkyl,phenylalkyl which is substituted by 1 to 5 independently selected R³²groups, alkenyl, cycloalkylalkyl, pyridylmethyl, furanylmethyl,thienylmethyl or thiazolylmethyl.
 40. The method of claim 39, whereinsaid optionally substituted phenylalkyl is optionally substituted benzylor optionally substituted phenylethyl, wherein the optional substituentsare 1 or 2 R³² groups independently selected from halo, alkyl, alkoxyand haloalkyl.
 41. The method of claim 39, wherein R is alkyl,alkoxyalkyl or cycloalkylalkyl and one R¹⁴ is hydrogen and the other ishydrogen or alkyl.
 42. The method of claim 38, wherein X is —N(R)— andeach R is independently selected from the group consisting of hydrogen,alkyl, alkoxyalkyl, cycloalkylalkyl and benzyl.
 43. The method of claim34, wherein R¹ is

and R is hydrogen, alkyl, alkoxyalkyl, cycloalkylalkyl or benzyl. 44.The method of claim 34, wherein R¹ is

and each R is independently selected from the group consisting ofhydrogen, alkyl, alkoxyalkyl, cycloalkylalkyl and benzyl; or R¹ is

and R is hydrogen, alkyl, alkoxyalkyl, cycloalkylalkyl or benzyl; or R¹is

wherein R⁴¹ is —C(O)-alkyl, —C(O)-cycloalkyl or —SO₂-alkyl; or R¹ is

wherein R is hydrogen, alkyl, alkoxyalkyl, cycloalkylalkyl or benzyl andR¹⁴ is alkoxy.
 45. The method of claim 34, wherein R⁶, R⁷, R⁸, R⁹, R¹²and R¹³ are each hydrogen, or R⁸, R⁹, R¹² and R¹³ are each hydrogen andR⁶ and R⁷ together are ═O.
 46. The method of claim 45, wherein R¹⁹ isoptionally substituted alkyl, —SO₂R¹⁸, pyridyl, oxazolyl, pyrazinyl,thienyl, or imidazolyl, wherein said pyridyl, said oxazolyl, saidpyrazinyl, said thienyl, and said imidazolyl are unsubstituted orsubstituted by from 1 to 5 independently selected R³² groups.
 47. Themethod of claim 45, wherein R¹⁹ is alkyl, benzyl, phenyl, pyridyl,oxazolyl, pyrazinyl, thienyl, or imidazolyl, wherein said benzyl, saidphenyl, said pyridyl, said oxazolyl, said pyrazinyl, said thienyl, andsaid imidazolyl are unsubstituted or substituted by from 1 to 5independently selected R³² groups, —SO₂alkyl, —SO₂phenyl, —SO₂benzyl,wherein said optional 1 to 5 R³² groups when present on phenyl areindependently selected from the group consisting of halo, alkyl, phenyl,alkoxy, haloalkyl, phenoxy, and —CN; wherein said optional 1 to 5 R³²groups when present on benzyl are independently selected from the groupconsisting of halo, alkyl, alkoxy, cyano and phenyl; and wherein saidpyridyl, said oxazolyl, said pyrazinyl, said thienyl, and saidimidazolyl (when present) are independently selected from alkyl, andhalo.
 48. The method of claim 34, wherein the cycloamino ring portion isselected from the groups consisting of:

wherein: R¹² is H or alkyl; and R¹⁹ is —SO₂R¹⁸, alkyl, pyridyl,oxazolyl, pyrazinyl, thienyl, or imidazolyl, wherein said alkyl, saidpyridyl, said oxazolyl, said pyrazinyl, said thienyl, and saidimidazolyl are unsubstituted or substituted by from 1 to 5 independentlyselected R³² groups.
 49. The method of claim 34, wherein R¹⁹ is alkyl,phenylalkyl or SO₂R¹⁸.
 50. The method of claim 34, wherein R¹⁹ isphenylalkyl.
 51. The method of claim 34, wherein R¹⁹ is phenyl orfluorobenzyl.
 52. The method of claim 34, wherein R¹⁹ is —SO₂R¹⁸ and R¹⁸is phenyl, pyridyl, thienyl or imidazolyl.
 53. The method of claim 49,wherein R⁶, R⁷, R⁸, R⁹, R¹² and R¹³ are each hydrogen.
 54. The method ofclaim 49, wherein R⁸, R⁹, R¹² and R¹³ are each hydrogen and R⁶ and R⁷together are ═O.
 55. The method of claim 49, wherein R⁶, R⁷, R⁹, and R¹³are each hydrogen; and R⁸ and R¹² are each independently selected fromthe group consisting of H and alkyl.
 56. The method of claim 49, whereinR⁸, R⁹, R¹², and R¹³ are H; and R⁶ and R⁷ together are ═O.
 57. Themethod of claim 34, having the stereochemical structure:


58. The method of claim 34, wherein said compound, or a pharmaceuticallyacceptable salt thereof, is selected from the group consisting of:


59. The method of claim 34, wherein said cognitive or neurodegenerativedisease is Alzheimer's disease.
 60. The method of claim 58, wherein saidcognitive or neurodegenerative disease is Alzheimer's disease.
 61. Amethod according to claim 34 or claim 58, wherein an effective amount ofsaid compound, or a pharmaceutically acceptable salt thereof, isadministered in combination with an effective amount of at least oneadditional active agent selected from the group consisting of: a BACE-1inhibitor other than those of Formula (I), an HMG-CoA reductaseinhibitor, a gamma-secretase inhibitor, a non-steroidalanti-inflammatory agent, an N-methyl-D-aspartate receptor antagonist, acholinesterase inhibitor and an anti-amyloid antibody.
 62. A method ofclaim 61, wherein said at least one additional active agent is at leastone HMG-CoA reductase inhibitor selected from the group consisting ofatorvastatin, lovastatin. simvistatin, pravastatin, fluvastatin androsuvastatin.
 63. A method of claim 61, wherein said at least oneadditional active agent is at least one cholinesterase inhibitorselected from the group consisting of tacrine, donepezil, rivastigmine,galantamine, pyridostigmine and neostigmine.
 64. A method of claim 61,wherein said at least one additional active agent is at least onenon-steroidal anti-inflammatory agent selected from the group consistingof ibuprofen, naproxen, diclofenac, diflunisal, etodolac, flurbiprofen,indomethacin, ketoprofen, ketorolac, nabumetone, oxaprozin, piroxicam,sulindac, tolmetin, celecoxib and rofecoxib.
 65. A method of claim 61,wherein said at least one additional active agent is at least oneN-methyl-D-aspartate receptor antagonist.
 66. A method of claim 61,wherein said at least one additional active agent is memantine.
 67. Amethod of inhibiting BACE-1 comprising contacting a population of cellsexpressing BACE-1, in vivo or in vitro, an effective amount of acompound, or a pharmaceutically acceptable salt thereof, said compoundhaving a structure according to Formula (I):

wherein: R¹ is

X is —O—, —C(R¹⁴)₂— or —N(R)—; Z is —C(R¹⁴)₂— or —N(R)—; t is 0, 1, 2 or3; each R is independently selected from the group consisting of H,alkyl, alkoxy, alkoxyalkyl, phenylalkyl, alkenyl, pyridylmethyl,furanylmethyl, thienylmethyl, thiazolylmethyl, cycloalkyl, andcycloalkylalkyl, wherein said alkyl, said alkoxy, said alkoxyalkyl, saidphenylalkyl, said alkenyl, said pyridylmethyl, said furanylmethyl, saidthienylmethyl, said thiazolylmethyl, said cycloalkyl, and saidcycloalkylalkyl are unsubstituted or substituted by from 1 to 5independently selected R³² groups; R² is H, alkyl, phenyl, orphenylalkyl, wherein said phenyl and said phenylalkyl are unsubstitutedor substituted by from 1 to 5 independently selected R³² groups; R³ is Hor alkyl; R⁴ is H or alkyl; R⁵ is H or alkyl; each R¹⁴ is independentlyselected from the group consisting of H, alkyl, alkenyl, halo, —CN,haloalkyl, phenyl, phenylalkyl, cycloalkyl, R⁴¹ is alkyl, cycloalkyl,—SO₂(alkyl), —C(O)-alkyl, —C(O)-cycloalkyl or -alkyl-NH—C(O)CH₃; R⁶ andR⁷ are independently selected from the group consisting of H and alkyl,or R⁶ and R⁷, together with the ring carbon to which they are attached,form —C(O)—; R⁸ and R⁹ are independently selected from the groupconsisting of H and alkyl, or R⁸ and R⁹, together with the ring carbonto which they are attached, form —C(O)—; R¹² and R¹³ are independentlyselected from the group consisting of H and alkyl, wherein said alkyl isunsubstituted or substituted by from 1 to 5 independently selected R³²groups, or R¹² and R¹³, together with the ring carbon to which they areattached, form —C(O)—; R¹⁸ is H, alkyl, phenyl, phenylalkyl, pyridyl,oxazolyl, pyrazinyl, thienyl, imidazolyl, pyridylalkyl, oxazolylalkyl,pyrazinylalkyl, thienylalkyl, or imidazolylalkyl, wherein said alkyl,said phenyl, said phenylalkyl, said pyridyl, said oxazolyl, saidpyrazinyl, said thienyl, said imidazolyl, said pyridylalkyl, saidoxazolylalkyl, said pyrazinylalkyl, said thienylalkyl, and saidimidazolylalkyl, are each unsubstituted or substituted by from 1 to 4independently selected R³² groups; R¹⁹ is H, alkyl, phenyl, phenylalkyl,pyridyl, oxazolyl, pyrazinyl, thienyl, imidazolyl, pyridylalkyl,oxazolylalkyl, pyrazinylalkyl, thienylalkyl, or imidazolylalkyl, —SOR¹⁸,—SO₂R¹⁸ or —CN, wherein said alkyl, said phenyl, said phenylalkyl, saidpyridyl, said oxazolyl, said pyrazinyl, said thienyl, said imidazolyl,said pyridylalkyl, said oxazolylalkyl, said pyrazinylalkyl, saidthienylalkyl, and said imidazolylalkyl, are each unsubstituted orsubstituted by from 1 to 4 independently selected R³² groups; and eachR³² group is independently selected from the group consisting of halo,alkyl, alkoxy, —OH, phenyl, phenoxy, phenylalkyl, —NO₂, —CN, haloalkyl,and haloalkoxy, or two R³² groups on the same ring carbon atom are takentogether to form ═O.
 68. A method of inhibiting the formation, or theformation and deposition of β-amyloid plaque in, on or aroundneurological tissue comprising administering to a patient in need ofsuch treatment an effective amount of a compound, or a pharmaceuticallyacceptable salt thereof, said compound having a structure according toFormula (I):

wherein: R¹ is

X is —O—, —C(R¹⁴)₂— or —N(R)—; Z is —C(R¹⁴)₂— or —N(R)—; t is 0, 1, 2 or3; each R is independently selected from the group consisting of H,alkyl, alkoxy, alkoxyalkyl, phenylalkyl, alkenyl, pyridylmethyl,furanylmethyl, thienylmethyl, thiazolylmethyl, cycloalkyl, andcycloalkylalkyl, wherein said alkyl, said alkoxy, said alkoxyalkyl, saidphenylalkyl, said alkenyl, said pyridylmethyl, said furanylmethyl, saidthienylmethyl, said thiazolylmethyl, said cycloalkyl, and saidcycloalkylalkyl are unsubstituted or substituted by from 1 to 5independently selected R³² groups; R² is H, alkyl, phenyl, orphenylalkyl, wherein said phenyl and said phenylalkyl are unsubstitutedor substituted by from 1 to 5 independently selected R³² groups; R³ is Hor alkyl; R⁴ is H or alkyl; R⁵ is H or alkyl; each R¹⁴ is independentlyselected from the group consisting of H, alkyl, alkenyl, halo, —CN,haloalkyl, phenyl, phenylalkyl, cycloalkyl, R⁴¹ is alkyl, cycloalkyl,—SO₂(alkyl), —C(O)-alkyl, —C(O)-cycloalkyl or -alkyl-NH—C(O)CH₃; R⁶ andR⁷ are independently selected from the group consisting of H and alkyl,or R⁶ and R⁷, together with the ring carbon to which they are attached,form —C(O)—; R⁸ and R⁹ are independently selected from the groupconsisting of H and alkyl, or R⁸ and R⁹, together with the ring carbonto which they are attached, form —C(O)—; R¹² and R¹³ are independentlyselected from the group consisting of H and alkyl, wherein said alkyl isunsubstituted or substituted by from 1 to 5 independently selected R³²groups, or R¹² and R¹³, together with the ring carbon to which they areattached, form —C(O)—; R¹⁸ is H, alkyl, phenyl, phenylalkyl, pyridyl,oxazolyl, pyrazinyl, thienyl, imidazolyl, pyridylalkyl, oxazolylalkyl,pyrazinylalkyl, thienylalkyl, or imidazolylalkyl, wherein said alkyl,said phenyl, said phenylalkyl, said pyridyl, said oxazolyl, saidpyrazinyl, said thienyl, said imidazolyl, said pyridylalkyl, saidoxazolylalkyl, said pyrazinylalkyl, said thienylalkyl, and saidimidazolylalkyl, are each unsubstituted or substituted by from 1 to 4independently selected R³² groups; R¹⁹ is H, alkyl, phenyl, phenylalkyl,pyridyl, oxazolyl, pyrazinyl, thienyl, imidazolyl, pyridylalkyl,oxazolylalkyl, pyrazinylalkyl, thienylalkyl, or imidazolylalkyl, —SOR¹⁸,—SO₂R¹⁸ or —CN, wherein said alkyl, said phenyl, said phenylalkyl, saidpyridyl, said oxazolyl, said pyrazinyl, said thienyl, said imidazolyl,said pyridylalkyl, said oxazolylalkyl, said pyrazinylalkyl, saidthienylalkyl, and said imidazolylalkyl, are each unsubstituted orsubstituted by from 1 to 4 independently selected R³² groups; and eachR³² group is independently selected from the group consisting of halo,alkyl, alkoxy, —OH, phenyl, phenoxy, phenylalkyl, —NO₂, —CN, haloalkyl,and haloalkoxy, or two R³² groups on the same ring carbon atom are takentogether to form ═O.